The Concise Guide to PHARMACOLOGY 2025/26: G protein-coupled receptors.

G protein-coupled receptors → G protein-coupled estrogen receptor The G protein-coupled estrogen receptor (GPER, nomenclature as agreed by the NC-IUPHAR Subcommittee on the G protein-coupled estrogen receptor [ 2291 ]) was identified following observations of estrogen-evoked cyclic AMP signalling in breast cancer cells [ 87 ], which mirrored the differential expression of an orphan 7-transmembrane receptor GPR30 [ 382 ]. There are observations of both cell-surface and intracellular expression of the GPER receptor [ 2371 , 2821 ]. Selective agonist/antagonists for GPER have been characterized [ 2291 ]. Antagonists of the nuclear estrogen receptor, such as fulvestrant [ 773 ], tamoxifen [ 2371 , 2821 ] and raloxifene [ 2233 ], as well as the flavonoid ‘phytoestrogens’ genistein and quercetin [ 1781 ], are agonists of GPER. Reviews of GPER pharmacology have been published [ 2291 ]. The roles of GPER in (patho)physiological systems throughout the body (cardiovascular, metabolic, endocrine, immune, reproductive) and in cancer have also been reviewed [ 772 , 1561 , 1882 , 2291 , 2292 ]. The GPER-selective agonist G-1 is currently in Phase I/II clinical trials for cancer ( NCT04130516 ).

G protein-coupled receptors → P2Y receptors P2Y receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [ 1 , 2 , 1253 ]) are activated by the endogenous ligands ATP , ADP , UTP , UDP , and UDP-sugars. The eight mammalian P2Y receptors are activated by distinct nucleotides: P2Y 1 , P2Y 11 , P2Y 12 and P2Y 13 are activated by adenosine-nucleotides; P2Y 2 , P2Y 4 can be activated by both adenosine and uridine nucleotides, with some species-specific differences; P2Y 6 is mainly activated by UDP; P2Y 14 is preferentially activated by sugar-uracil nucleotides. The missing numbers in the receptor nomenclature refer either to non-mammalian orthologs or receptors having some sequence homology to P2Y receptors but for which there is no functional evidence of responsiveness to nucleotides [ 2958 ]. Based on their G protein coupling P2Y receptors can be divided into two subfamilies: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 and P2Y 11 receptors couple via Gq proteins to stimulate phospholipase C followed by increases in inositol phosphates and mobilization of Ca 2+ from intracellular stores. P2Y 11 receptors couple in addition to Gs proteins followed by increased adenylate cyclase activity. In contrast, P2Y 12 , P2Y 13 , and P2Y 14 receptors signal primarily through activation of Gi proteins and inhibition of adenylate cyclase activity or control of ion channel activity [ 2958 ]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol , agonist of the P2Y 2 receptor subtype, approved in Japan and South Korea for the management of dry eye disease [ 1566 ], and the P2Y 12 receptor antagonists clopidogrel , prasugrel , cangrelor and ticagrelor , all approved as antiplatelet drugs [ 376 , 2281 ]. A series of 4-alkyloxyimino derivatives of uridine-5’-triphosphate which could be useful for derivatization as fluorescent P2Y 2/4/6 receptor probes has been synthesized [ 1276 ]. Recently, selatogrel, a potent and reversible P2Y 12 receptor antagonist in clinical trials for acute myocardial infarction and chronic coronary syndromes, showed potent platelet inhibition, rapid onset, suitable duration, and good safety [ 2624 , 2704 ]. Cryo-EM structures of the apo P2Y 2 receptor in complex with G q , the ATP-bound P2Y 2 receptor in complex with G q or G o , and the UTP-bound P2Y 4 receptor in complex with G q have been determined [ 1547 ]. A helix-like segment within the N-terminus of the apo P2Y 2 receptor has been found to occupy the orthosteric ligand-binding pocket, revealing a novel mechanism of receptor self-activation [ 1547 ]. The human P2Y 12 receptor has been structurally resolved in complex with the antagonist AZD1283 [ 3230 ] and the agonist 2MeSADP [ 3228 ]. Single nucleotide polymorphisms of the P2YR 1 gene have been associated to different platelet reactivity to ADP [ 1117 ]. Three frequent nonsynonymous P2Y 2 receptor polymorphisms have been identified, one of which was significantly more common in cystic fibrosis patients. This polymorphism is linked to increases in Ca 2+ influx in transfected cells, and might therefore play a role in disease development [ 348 ]. ATP acts as partial agonist/antagonist at the human P2Y 4 receptor [ 2958 ]. A frequent loss-of-function P2Y 4 variant was found associated with less severe coronary artery atherosclerosis and lower fasting plasma glucose in coronary patients [ 1163 ]. A group of single nucleotide polymorphisms in the P2Y 12 gene, forming the so called P2Y 12 H2 haplotype, has been associated with increased platelet responsiveness to ADP, increased risk of peripheral arterial disease and with coronary artery disease [ 401 ]. The platelet-type bleeding disorder due to P2Y 12 receptor defects is an autosomal recessive condition characterized by mild to moderate mucocutaneous bleeding and excessive bleeding after surgery or trauma. The defect is due to the inability of ADP to induce platelet aggregation [ 397 ]. The P2Y 13 receptor Met-158-Thr polymorphism, which is in linkage disequilibrium with the P2Y 12 locus, is not associated with acute myocardial infarction, diabetes mellitus or related risk factors [ 60 ]. The P2Y 14 receptor, previously known to bind sugar nucleotides such as UDP-glucose and its derivatives, has also been shown to bind UDP [ 390 ], which competitively antagonizes the UDP-glucose response at the human recombinant receptor [ 819 ].

G protein-coupled receptors → VIP and PACAP receptors Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors [ 1054 , 1055 ]) are activated by the endogenous peptides VIP ( VIP , P01282 ), PACAP-38 ( ADCYAP1 , P18509 ), PACAP-27 ( ADCYAP1 , P18509 ), peptide histidine isoleucineamide ( PHI {Mouse, Rat}), peptide histidine methionineamide ( PHM ( VIP , P01282 )) and peptide histidine valine ( PHV ( VIP , P01282 )). VPAC 1 and VPAC 2 receptors display comparable affinity for the PACAP peptides, PACAP-27 ( ADCYAP1 , P18509 ) and PACAP-38 ( ADCYAP1 , P18509 ), and VIP ( VIP , P01282 ), whereas PACAP-27 ( ADCYAP1 , P18509 ) and PACAP-38 ( ADCYAP1 , P18509 ) are >100 fold more potent than VIP ( VIP , P01282 ) as agonists of most isoforms of the PAC 1 receptor. However, one splice variant of the human PAC 1 receptor has been reported to respond to PACAP-38 ( ADCYAP1 , P18509 ), PACAP-27 ( ADCYAP1 , P18509 ) and VIP ( VIP , P01282 ) with comparable affinity [ 583 ]. PG 99–465 [ 1960 ] has been used as a selective VPAC 2 receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC 1 and PAC 1 receptors [ 644 ]. The selective PAC 1 receptor agonist maxadilan , was extracted from the salivary glands of sand flies ( Lutzomyia longipalpis ) and has no sequence homology to VIP ( VIP , P01282 ) or the PACAP peptides [ 1977 ]. Two deletion variants of maxadilan, M65 [ 2880 ] and Max.d.4 [ 1978 ] have been reported to be PAC 1 receptor antagonists, but these peptides have not been extensively characterised. Subtypes of PAC 1 receptors have been proposed based on tissue differences in the potencies of PACAP-27 ( ADCYAP1 , P18509 ) and PACAP-38 ( ADCYAP1 , P18509 ); these might result from differences in G protein coupling and second messenger mechanisms [ 2917 ], or from alternative splicing of PAC 1 receptor mRNA [ 2675 ].

G protein-coupled receptors → Bile acid receptor The bile acid receptor (GPBA) responds to bile acids produced during the liver metabolism of cholesterol . Selective agonists are promising drugs for the treatment of metabolic disorders, such as type II diabetes, obesity and atherosclerosis. The triterpenoid natural product betulinic acid has also been reported to inhibit inflammatory signalling through the NFκB pathway [ 2761 ]. Disruption of GPBA expression is reported to protect from cholesterol gallstone formation [ 2933 ]. A new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides have been reported as highly potent agonists [ 1727 ].

G protein-coupled receptors → Free fatty acid receptors Free fatty acid receptors (FFA, nomenclature as agreed by the NC-IUPHAR Subcommittee on free fatty acid receptors [ 586 , 2703 ]) are activated by free fatty acids. Long-chain saturated and unsaturated fatty acids (including C14.0 ( myristic acid ), C16:0 ( palmitic acid ), C18:1 ( oleic acid ), C18:2 ( linoleic acid ), C18:3, ( α-linolenic acid ), C20:4 ( arachidonic acid ), C20:5,n-3 ( EPA ) and C22:6,n-3 ( docosahexaenoic acid )) activate FFA1 [ 308 , 1241 , 1483 ] and FFA4 receptors [ 1130 , 1208 , 2111 ], while short chain fatty acids (C2 ( acetic acid ), C3 ( propanoic acid ), C4 ( butyric acid ) and C5 ( pentanoic acid )) activate FFA2 [ 319 , 1585 , 2078 ] and FFA3 [ 319 , 1585 ] receptors. The crystal structure for agonist bound FFA1 has been described [ 2679 ]. Short (361 amino acids) and long (377 amino acids) splice variants of human FFA4 have been reported [ 1958 ], which differ by a 16 amino acid insertion in intracellular loop 3, and exhibit differences in intracellular signalling properties in recombinant systems [ 3031 ]. The long FFA4 splice variant has not been identified in other primates or rodents to date [ 1130 , 1958 ]. GPR42 was originally described as a pseudogene within the family ( ENSFM00250000002583 ), but the discovery of several polymorphisms suggests that some versions of GPR42 may be functional [ 1666 ]. GPR84 is a structurally-unrelated G protein-coupled receptor which has been found to respond to medium chain fatty acids [ 2996 ].

G protein-coupled receptors → GABA B receptors Functional GABA B receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on GABA B receptors [ 280 , 2247 ]) are formed from the heterodimerization of two similar 7TM subunits termed GABA B1 and GABA B2 [ 280 , 721 , 2246 , 2247 , 2889 ]. GABA B receptors are widespread in the CNS and regulate both pre- and postsynaptic activity. The GABA B1 subunit, when expressed alone, binds both antagonists and agonists, but the affinity of the latter is generally 10–100-fold less than for the native receptor. Co-expression of GABA B1 and GABA B2 subunits allows transport of GABA B1 to the cell surface and generates a functional receptor that can couple to signal transduction pathways such as high-voltage-activated Ca 2+ channels (Ca v 2.1, Ca v 2.2), or inwardly rectifying potassium channels (Kir3) [ 213 , 280 , 281 ]. The GABA B1 subunit harbours the GABA (orthosteric)-binding site within an extracellular domain (ECD) venus flytrap module (VTM), whereas the GABA B2 subunit mediates G protein-coupled signalling [ 280 , 885 , 887 , 2246 ]. The cryo-electron microscopy structures of the human full-length GABA B1 -GABA B2 heterodimer have been solved in the inactive apo state, two intermediate agonist-bound forms and an active state in which the heterodimer is bound to an agonist and a positive allosteric modulator [ 2577 ]. Phospholipids bound within the central cavity of the transmembrane domains stabilize the inactive state. The positive allosteric modulator binds to the transmembrane interface and stabilizes the active state. Recent evidence indicates that higher order assemblies of GABA B receptors comprising dimers of heterodimers occur in recombinant expression systems and in vivo , and that such complexes exhibit negative functional cooperativity between heterodimers [ 528 , 2244 ]. Adding further complexity, KCTD (potassium channel tetramerization proteins) 8, 12, 12b and 16 associate as tetramers with the carboxy terminus of the GABA B2 subunit to impart altered signalling kinetics and agonist potency to the receptor complex [ 156 , 2537 , 2875 ] and are reviewed by [ 2248 ]. The molecular complexity of GABA B receptors is further increased through association with trafficking and effector proteins [ 2538 ] and reviewed by [ 2243 ]. The predominant GABA B1a and GABA B1b isoforms, which are most prevalent in neonatal and adult brain tissue respectively, differ in their ECD sequences as a result of the use of alternative transcription initiation sites. GABA B1a -containing heterodimers localise to distal axons and mediate inhibition of glutamate release in the CA3-CA1 terminals, and GABA release onto the layer 5 pyramidal neurons, whereas GABA B1b -containing receptors occur within dendritic spines and mediate slow postsynaptic inhibition [ 2212 , 2942 ]. Amyloid precursor protein (APP) and soluble APP (sAPP) bind to the N-terminal sushi domain of the GABA B1a isoform to regulate axonal trafficking of GABA B receptors and release of neurotransmitters [ 2384 ]. AJAP1 ( Q9UKB5 ) is a dendritic protein that trans-synaptically recruits GABA B1a -containing receptors to presynaptic sites [ 801 ]. Missense variants in GABABR and AJAP1 genes as well as autoantibodies link receptor dysfunction to neurodevelopmental disorders and epileptic encephalopathies [ 405 , 801 , 1550 ].

Numbers in brackets refer to orphan receptors for which an endogenous ligand has been proposed in at least one publication, see [ 586 ] [ 2130 ] [ 1943 ] [ 2803 ].

G protein-coupled receptors → Class A Orphans → LGR4, LGR5, LGR6 This set of orphan GPCRs contain leucine rich repeat domains which suggests potential for participation in protein-protein interactions. LGR4/5/6 have been identified as components of the Wnt/β-catenin signaling complexes [ 146 , 2592 , 2905 , 3000 ]. LGR4 and −5 are recognised as markers of cancer stem cells. These receptors are active targets for anti-tumour drug development [ 445 , 1109 , 1746 , 2840 , 2841 ].

G protein-coupled receptors → Class A Orphans → Mas1, BB3/brs3, GPR17 These 3 orphan GPCRs are considered ‘foster children’ of well established GPCR families and are reviewed by the corresponding subcommittee members; Mas1 (Angiotensin receptors), BB 3 receptor (Bombesin receptors), GPR17 (P2Y receptors/Leukotriene receptors).

G protein-coupled receptors → QRFP receptor The human gene encoding the QRFP receptor ( nomenclature as agreed by the NC-IUPHAR Subcommittee on the QRFP receptor [ 1629 ]; QRFPR, formerly known as the Peptide P518 receptor), previously designated as an orphan GPCR receptor was identified in 2001 by Lee et al. from a hypothalamus cDNA library [ 1599 ]. However, the reported cDNA ( AF411117 ) is a chimera with bases 1–127 derived from chromosome 1 and bases 155–1368 derived from chromosome 4. When corrected, QRFPR (also referred to as SP9155 or AQ27) encodes a 431 amino acid protein that shares sequence similarities in the transmembrane spanning regions with other peptide receptors. These include neuropeptide FF2 (38%), neuropeptide Y 2 (37%) and galanin Gal 1 (35%) receptors. QRFP receptor was identified as a Gs-coupled GPCR [ 430 , 1289 ] that’s activated by the endogenous peptides QRFP43 (43RFa) and QRFP26 (26RFa) [ 430 , 829 , 1289 ]. However, Gq- and Gi/o-mediated signaling was also reported [ 829 , 2335 ]. Two naturally occurring mutations in the human QRFP receptor lead to distinct and opposite 26RFa-evoked signaling bias [ 1762 ]. The orphan receptor GPR83 ( 9NYM4 ) shows sequence similarities with the QRFP receptor, as well as with the NPFF1, NPFF2, and PrRP receptors.

G protein-coupled receptors → Class Frizzled GPCRs Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [ 2531 ]), are GPCRs highly conserved across species and were originally identified in Drosophila [ 416 ]. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it is involved in Hedgehog signaling [ 2531 ]. SMO exerts its effects by activating heterotrimeric G proteins or stabilization of GLI by sequestering catalytic PKA subunits [ 89 , 1047 , 2581 ]. While SMO itself is bound by sterols and oxysterols [ 537 , 1423 ], FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in ontogeny and tissue homeostasis. FZD signaling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator β-catenin ( CTNNB1 , P35222 ) or being β-catenin-independent (often referred to as canonical vs. non-canonical WNT/FZD signaling, respectively). Nevertheless, it makes pharmacologically more sense to define downstream signaling by transducer coupling to either DVL or heterotrimeric G proteins [ 2532 ]. WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors LRP5 ( O75197 ) and LRP6 ( O75581 ), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin and subsequently its translocation to the nucleus. β-catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. WNT/β-catenin-dependent signalling can also be activated by FZD subtype-specific WNT surrogates [ 1890 ]. β-catenin-independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of heterotrimeric G proteins [ 648 , 2226 , 2533 ], the elevation of intracellular calcium [ 2637 ], activation of cGMP-specific PDE6 [ 25 ] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [ 1042 ]. Novel resonance energy transfer-based tools have allowed the study of the GPCR-like nature of FZDs in greater detail. Upon ligand stimulation, FZDs undergo conformational changes and signal via heterotrimeric G proteins [ 282 , 958 , 1488 , 1491 , 2508 , 3098 , 3099 ]. Furthermore, the phosphoprotein Dishevelled constitutes a key transducer in WNT/FZD signaling towards planar-cell-polarity-like pathways. Importantly, FZDs adopt distinct conformational landscapes that regulate pathway selection [ 956 , 3099 ]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [ 450 ], as well as for β-catenin-dependent [ 333 ] and -independent [ 334 , 1402 ] signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled-related proteins (sFRP), Wnt-inhibitory factor ( WIF1 , Q9Y5W5 ) (WIF), sclerostin ( SOST , Q9BQB4 ) or Dickkopf (DKK)), as well as modulatory (co)-receptors with Ryk , ROR1 , ROR2 and PTK7, which may also function as independent signaling proteins. An important FZD 4 -selective non-WNT agonist is the norrin ( NDP , Q00604 ) cysteine knot protein, which is a key player in FZD 4 -mediated vascularization for example in the retina and which is functionally related to familial exudative vitreoretinopathy (FEVR). There is limited knowledge about WNT/FZD specificity and which molecular entities determine the signalling outcome of a specific WNT/FZD pair. Recent insights into protein dynamics, activation mechanisms, conserved microswitches, and co-receptor involvement of FZDs have advanced our understanding in being able to target this enigmatic class of receptors as drug targets [ 282 , 956 , 958 , 1426 , 2961 ]. Findings with recent reported small molecules were not reproducible, including FzM1.8 and carbamazepine, highlighting the limitations in the assays available [ 1427 , 2824 ]. Understanding of FZD and SMO coupling to heterotrimeric G proteins is incomplete, but progress has been made [ 88 , 628 , 648 , 1398 , 1805 , 2306 , 2307 , 2395 , 2581 , 2959 , 3098 ]. Development of pharmacological tools [ 1490 ] for SMO has been faciliated by successful determination of several SMO structures [ 356 , 628 , 1191 , 1490 , 2306 , 2307 , 2985 , 2986 , 3229 , 3240 ]. The increase in FZD structures including FZD 1,3,6,7 in apo and active states and a recent FZD 4 complex with DEP have provided insights into FZD transmembrane organization and intracellular transducer coupling [ 1426 , 2309 , 2872 , 3132 , 3168 , 3244 ]. FZD 7 has emerged as a particularly interesting WNT receptor by primarily modulating carcinogenesis, metastasis, and chemoresistance [ 1564 ]. Recent pharmacological and structural studies highlight FZD 7 in the context of intenstinal cancer and its interaction with the virulence factor, TcdB [ 957 , 1426 ].

G protein-coupled receptors → GPR18, GPR55 and GPR119 GPR18 , GPR55 and GPR119 ( provisional nomenclature ), although showing little structural similarity to CB 1 and CB 2 cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [ 2223 ]. Although there are multiple reports to indicate that GPR18 , GPR55 and GPR119 can be activated in vitro by N-arachidonoylglycine , lysophosphatidylinositol and N-oleoylethanolamide , respectively, there is a lack of evidence for activation by these lipid messengers in vivo . As such, therefore, these receptors retain their orphan status. GPR18 failed to respond to a variety of lipid-derived agents in an in vitro screen [ 3184 ], but has been reported to be activated by Δ 9 -tetrahydrocannabinol [ 1864 ]. GPR55 responds to AM251 and rimonabant at micromolar concentrations, compared to their nanomolar affinity as CB 1 receptor antagonists/inverse agonists [ 2223 ]. It has been reported that lysophosphatidylinositol acts at other sites in addition to GPR55 [ 3150 ]. N-Arachidonoylserine has been suggested to act as a low efficacy agonist/antagonist at GPR18 in vitro [ 1862 ]. It has also been suggested oleoyl-lysophosphatidylcholine acts, at least in part, through GPR119 [ 2079 ]. Although PSN375963 and PSN632408 produce GPR119 -dependent responses in heterologous expression systems, comparison with N-oleoylethanolamide -mediated responses suggests additional mechanisms of action [ 2079 ].

G protein-coupled receptors → Class A Orphans → GPR42, GPR84 There is some evidence to suggest that GPR42 and GPR84 may be free fatty acid receptors.

G protein-coupled receptors → Opsin receptors

G protein-coupled receptors → Other non-GPCR 7TM proteins Overview : These proteins are predicted to have 7TM domains, but functional studies have yet to confirm them as G protein-coupled receptors.

G protein-coupled receptors → TAAR2, TAAR3, TAAR4p, TAAR5, TAAR6, TAAR8, TAAR9 This set of orphan GPCRs are under review by the NC-IUPHAR subcommittee for the Trace amine receptors.

G protein-coupled receptors → Taste 2 receptors Taste 2 receptors or Bitter taste receptors (TAS2Rs) are G protein-coupled receptors expressed in oral sensory cells and a variety of non-gustatory tissues. The ~25 human TAS2Rs share low amino acid sequence identities with other GPCR families and are classified as broadly tuned “generalist” receptors with numerous, chemically diverse bitter agonists, as narrowly tuned “specialist” receptors with very few activators, as intermediately tuned receptors with an average number of agonists, or receptors specialized to interact with chemically defined activators [ 1885 ]. The number of functional bitter taste receptor genes varies among species and orthologues might not be functionally conserved. Due to their expression in various tissues, the signal transduction of TAS2Rs is complex. Some TAS2Rs interact with drugs such as analgesic, anti-inflammatory, and antibacterial compounds. The specialist database BitterDB contains additional information on bitter compounds and receptors [ 570 ]. Recently, several experimental cryo-electron structures of TAS2Rs have been published [ 2213 ].

G protein-coupled receptors → Trace amine receptor Trace amine-associated receptors were discovered from a search for novel 5-HT receptors [ 269 ], where 15 mammalian orthologues were identified and divided into two families. The TA 1 receptor ( nomenclature as agreed by the NC-IUPHAR Subcommittee for the Trace amine receptor [ 1784 ]) has affinity for the endogenous trace amines tyramine , β-phenylethylamine and octopamine in addition to the classical amine dopamine [ 269 ]. Emerging evidence suggests that TA 1 is a modulator of monoaminergic activity in the brain [ 3124 ] with TA 1 and dopamine D 2 receptors shown to form constitutive heterodimers when co-expressed [ 736 ]. In addition to trace amines, receptors can be activated by amphetamine-like psychostimulants, and endogenous thyronamines. In addition to TA 1 , in man there are up to 5 functional TAAR genes (TAAR2,5,6,8,9). See [ 269 ] for detailed discussion. The product of the gene TAAR2 (also known as GPR58) appears to respond to β-phenylethylamine > tyramine and to couple through G s [ 269 ]. TAAR3 , in some individuals, and TAAR4 are pseudogenes in man, although functional in rodents. The signalling characteristics and pharmacology of TAAR 5 (PNR, Putative Neurotransmitter Receptor: TAAR5 , O14804 ), TAAR 6 (Trace amine receptor 4, TaR-4: TAAR6 , 96RI8 ), TAAR 8 (Trace amine receptor 5, GPR102: TAAR8 , Q969N4 ) and TAAR 9 (trace amine associated receptor 9: TAAR9 , 96RI9 ) are lacking. The thyronamines, endogenous derivatives of thyroid hormone, have affinity for rodent cloned trace amine receptors, including TA 1 [ 2495 ]. An antagonist EPPTB has recently been described with a p K i of 9.1 at the mouse TA 1 but >5.3 for human TA 1 [ 2686 ].

G protein-coupled receptors → Apelin receptor The apelin receptor ( nomenclature as agreed by the NC-IUPHAR Subcommittee on the apelin receptor [ 2252 ] and subsequently updated [ 2361 ]) responds to apelin, a 36 amino-acid peptide derived initially from bovine stomach. Apelin-36 ( APLN , Q9ULZ1 ), apelin-13 ( APLN , Q9ULZ1 ) and [Pyr 1 ]apelin-13 ( APLN , Q9ULZ1 ) are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide ( APLN , Q9ULZ1 ) [ 2798 ]. A second family of peptides discovered independently and named Elabela [ 478 ] or Toddler, that has little sequence similarity to apelin, is present, and functional at the apelin receptor in the adult cardiovascular system [ 2187 , 3167 ]. The enzymatic pathways generating biologically active apelin and Elabela isoforms have not been determined but both propeptides include sites for potential proprotein convertase processing [ 2596 ]. Structure-activity relationship Elabela analogues have been described [ 2006 , 2863 ]. The stoichiometry of apelin receptor-heterotrimeric G protein complexes has been studied using cryogenic-electron microscopy [ 3206 ]. A crystal structure for the apelin receptor in complex with a G protein-biased agonist has been reported [ 3075 ]. Potency order determined for heterologously expressed human apelin receptor (p D 2 values range from 9.5 to 8.6). The apelin receptor may also act as a co-receptor with CD4 for isolates of human immunodeficiency virus, with apelin blocking this function [ 403 ]. A modified apelin-13 peptide, apelin-13(F13A) was reported to block the hypotensive response to apelin in rat in vivo [ 1600 ], however, this peptide exhibits agonist activity in HEK293 cells stably expressing the recombinant apelin receptor [ 748 ]. The apelin receptor antagonist, MM54, was reported to suppress tumour growth and increase survival in an intracranial xenograft mouse model of glioblastoma [ 1050 ].

G protein-coupled receptors → GPR143 GPR143 is an orphan GPCR with a preliminary pairing for an endogenous candidate. NC-IUPHAR considers it to be structurally distinct from existing classes of GPCR.

G protein-coupled receptors → Opioid receptors Opioid and opioid-like receptors are activated by a variety of endogenous peptides including [Met]enkephalin ( PENK , P01210 ) (met), [Leu]enkephalin ( PENK , P01210 ) (leu), β-endorphin ( POMC , P01189 ) (β-end), α-neodynorphin ( PDYN , P01213 ), dynorphin A ( PDYN , P01213 ) (dynA), dynorphin B ( PDYN , P01213 ) (dynB), big dynorphin ( PDYN , P01213 ) (Big dyn), nociceptin/orphanin FQ ( PNOC , Q13519 ) (N/OFQ); endomorphin-1 and endomorphin-2 are also potential endogenous peptides. The Greek letter nomenclature for the opioid receptors, μ, δ and κ, is well established, and NC-IUPHAR considers this nomenclature appropriate, along with the symbols spelled out (mu, delta, and kappa), and the acronyms, MOP, DOP, and KOP [ 550 , 633 , 789 ]. However the acronyms MOR, DOR and KOR are still widely used in the literature. The human N/OFQ receptor, NOP, is considered ‘opioid-related’ rather than opioid because, while it exhibits a high degree of structural homology with the conventional opioid receptors [ 550 , 1942 ], it displays a distinct pharmacology. Currently there are numerous clinically used drugs, such as morphine and many other opioid analgesics, as well as antagonists such as naloxone . The majority of clinically used opiates are relatively selective μ agonists or partial agonists, though there are some μ/κ compounds, such as butorphanol , in clinical use. κ opioid agonists, such as the alkaloid nalfurafine and the peripherally acting peptide difelikefalin , are in clinical use for itch. Three genes for naloxone-sensitive opioid receptors have been identified in humans, and while the μ receptor in particular may be subject to extensive alternative splicing [ 2175 ], these putative isoforms have not been correlated with any of the subtypes of receptor proposed in years past. Opioid receptors may heterodimerize with each other or with other 7TM receptors [ 1310 ], and give rise to complexes with a unique pharmacology, however, evidence for such heterodimers in native cells is equivocal and the consequences of this heterodimerization for signalling remains largely unknown. For μ-opioid receptors at least, dimerization does not seem to be required for signalling [ 1531 ]. A distinct met-enkephalin receptor lacking structural resemblance to the opioid receptors listed has been identified ( OGFR , 9NZT2 ) and termed an opioid growth factor receptor [ 3210 ]. endomorphin-1 and endomorphin-2 have been identified as highly selective, putative endogenous agonists for the μ-opioid receptor. At present, however, the mechanisms for endomorphin synthesis in vivo have not been established, and there is no gene identified that encodes for either. Thus, the status of these peptides as endogenous ligands remains unproven. Two areas of increasing importance in defining opioid receptor function are the presence of functionally relevant single nucleotide polymorphisms in human μ-receptors [ 2107 ] and the identification of biased signalling by opioid receptor ligands, both agonists and antagonists [ 325 , 1370 ]. Despite the identification of biased ligands for the μ receptor, the relevance with respect to physiological and behavioral actions in vivo is not clear [ 912 ]. Pathway bias for agonists makes general rank orders of potency and efficacy somewhat obsolete, so these do not appear in the table. As ever, the mechanisms underlying the acute and long term regulation of opiod receptor function are the subject of intense investigation and debate. The richness of opioid receptor pharmacology has been enhanced with the recent discovery of allosteric modulators of μ and δ receptors, notably the positive allosteric modulators and silent allosteric “antagonists” outlined in [ 341 , 342 ]. Negative allosteric modulation of opioid receptors has been previously suggested [ 1354 ], whether all compounds are acting at a similar site remains to be established. In the last decade, several opioid receptors structures have been solved in their inactive and active forms: δ receptor [ 762 , 763 , 963 , 3015 ]; κ receptor [ 433 , 434 , 3015 , 3104 ]; μ receptor [ 749 , 1193 , 1455 , 1803 , 2312 , 2405 , 2989 , 3015 , 3271 ]; NOP [ 1911 , 2822 , 3015 ]. More recently, and importantly, cryoEM has been used to identify ligand-receptor interactions and design novel ligands [ 1339 , 2928 ].

G protein-coupled receptors → Orexin receptors Orexin receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [ 1516 ]) are activated by the endogenous polypeptides orexin-A ( HCRT , O43612 ) and orexin-B ( HCRT , O43612 ) (also known as hypocretin-1 and −2; 33 and 28 aa) derived from a common precursor, prepro-orexin or orexin precursor , by proteolytic cleavage and some typical peptide modifications [ 1516 , 2460 ]. Orexin signaling has been associated with regulation of sleep and wakefulness, reward and addiction, appetite and feeding, pain gating, stress response, anxiety and depression. Currently the orexin receptor ligands in clinical use are the dual orexin receptor antagonists suvorexant , lemborexant and daridorexant , which are used as hypnotics, and several dual, as well as OX 1 - and OX 2 -selective antagonists are under development for different indications. Multiple orexin agonists are in development for the treatment of narcolepsy and other sleep disorders. Orexin receptor 3D structures have been solved [ 90 , 1101 , 1159 , 2344 , 2735 , 3185 , 3187 , 3188 ]. The primary coupling of orexin receptors to G q/11 proteins is rather speculative and based on the strong activation of phospholipase C, though recent studies in recombinant cells also stress the importance of G q/11 [ 1513 ]. Coupling of both receptors to G i/o , G s and and G 12/13 has also been reported [ 1228 , 1352 , 1517 , 1624 , 2341 ]. For most native cellular responses observed, the G protein pathway is unknown. The selectivity of agonist ligands may depend on the cellular signal transduction machinery [ 1514 , 2303 , 2394 , 3143 ]. Thorough characterization of many antagonists and radioligands has not been published, but the situation has recently improved for many commercially available ones. Orexin receptors have been reported to be able to form complexes with each other and some other GPCRs as well as σ1-receptors , which might affect the signaling and pharmacology [ 1515 , 2035 ].

G protein-coupled receptors → Galanin receptors Galanin receptors ( provisional nomenclature as recommended by NC-IUPHAR [ 789 ]) are activated by the endogenous peptides galanin ( GAL , P22466 ) and galanin-like peptide ( GALP , Q9UBC7 ). Human galanin ( GAL , P22466 ) is a 30 amino-acid non-amidated peptide [ 743 ]; in other species, it is 29 amino acids long and C-terminally amidated. Amino acids 1–14 of galanin are highly conserved in mammals, birds, reptiles, amphibia and fish. Shorter peptide species ( e.g . human galanin-1–19 [ 208 ] and porcine galanin-5–29 [ 2612 ]) and N-terminally extended forms ( e.g. N-terminally seven and nine residue elongated forms of porcine galanin [ 209 , 2612 ]) have been reported. More recently, the newly-identified peptide, spexin (SPX), has been reported to activate human GAL2 and GAL3 (but not GAL1) receptors in heterologous expression systems; and to alter GAL2/3 receptor-related behaviours in animals [ 1401 ]. Galanin and spexin neuropeptides are important regulators of energy homeostasis [ 838 ]. Galanin-(1–11) is a high-affinity agonist at GAL 1 /GAL 2 (p K i 9), and galanin(2–11) is selective for GAL 2 and GAL 3 compared with GAL 1 [ 1738 ]. [ 125 I]-[Tyr 26 ]galanin binds to all three subtypes with K d values generally reported to range from 0.05 to 1 nM, depending on the assay conditions used [ 784 , 2629 , 2644 , 2645 , 3006 ]. Porcine galanin-(3–29) does not bind to cloned GAL 1 , GAL 2 or GAL 3 receptors, but a receptor that is functionally activated by porcine galanin-(3–29) has been reported in pituitary and gastric smooth muscle cells [ 987 , 3116 ]. Additional galanin receptor subtypes are also suggested from studies with chimeric peptides ( e.g . M15 , M35 and M40 ), which act as antagonists in functional assays in the cardiovascular system [ 2887 ], spinal cord [ 3068 ], locus coeruleus, hippocampus [ 154 ] and hypothalamus [ 155 , 1618 ], but exhibit agonist activity at some peripheral sites [ 155 , 987 ]. The chimeric peptides M15 , M32 , M35 , M40 and C7 are agonists at GAL 1 receptors expressed endogenously in Bowes human melanoma cells [ 2118 ], and at heterologously expressed recombinant GAL 1 , GAL 2 and GAL 3 receptors [ 784 , 2644 , 2645 ]. Further studies described the synthesis of a series of novel, systemically-active, galanin analogues, with modest preferential binding at the GAL 2 receptor. Specific chemical modifications to the galanin backbone increased brain levels of these peptides after i.v. injection and several of these peptides exerted a potent antidepressant-like effect in mouse models of depression [ 2452 ]. More recent studies have identified synthetic spexin (SPX)-based peptides that are selective GAL 2 receptor agonists [ 1607 , 2374 ].

G protein-coupled receptors → Ghrelin receptor The ghrelin receptor ( nomenclature as agreed by the NC-IUPHAR Subcommittee for the Ghrelin receptor [ 587 ]) is activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 amino-acid precursor ( GHRL , Q9UBU3 ). A unique post-translational modification (octanoylation of Ser 3 , catalysed by ghrelin Ο-acyltransferase ( MBOAT4 , Q96T53 ) [ 3161 ] is essential for binding and activation of ghrelin receptors in all tissues, including the hypothalamus and pituitary [ 1463 ]. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding [ 175 ], and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin ( GHRL , Q9UBU3 ) function [ 1155 ]. The authorities in Japan have in 2020 approved the orally active agonist anamorelin, for the treatment of anorexia in cancer patients [ 2971 ]. PF-05190457 is a small-molecule inverse agonist targeting the ghrelin receptor that has been progressed to phase I clinical trial for the treatment of alcoholism and has been demonstrated to decrease appetite [ 752 ]. An endogenous antagonist and inverse agonist called Liver enriched antimicrobial peptide 2 (Leap2), expressed primarily in hepatocytes and in enterocytes of the proximal intestine [ 878 , 1758 ] inhibits ghrelin receptor-induced GH secretion and food intake [ 878 ]. The secretion of Leap2 and ghrelin is inversely regulated under various metabolic conditions [ 1804 ]. In cell systems the ghrelin receptor is constitutively active [ 1156 ], and this property is responsible for modulation of D 2 receptor signalling [ 615 ], and is attenuated by a naturally occurring mutation (A204E) that is associated with familial short stature [ 2167 ]. A potent inverse agonist has been identified ( [D-Arg 1 ,D-Phe 5 ,D-Trp 7,9 ,Leu 11 ]substance P , p D 2 8.3; [ 1153 ]). Ulimorelin , described as a ghrelin receptor agonist (p K i 7.8 and p D 2 7.5 at human recombinant ghrelin receptors), has been shown to stimulate ghrelin receptor mediated food intake and gastric emptying but not elicit release of growth hormone, or modify ghrelin stimulated growth hormone release, thus pharmacologically discriminating the orexigenic and gastrointestinal actions of ghrelin ( GHRL , Q9UBU3 ) from the release of growth hormone [ 805 ]. Similar discrimination of ghrelin receptor mediated physiological functions can be obtained by activation of distinct signaling pathways [ 1875 ]. A number of selective antagonists have been reported, including peptidomimetic [ 1988 ] and non-peptide small molecules including GSK1614343 [ 2190 , 2210 , 2453 ].

G protein-coupled receptors → Motilin receptor Motilin receptors ( provisional nomenclature ) are activated by motilin ( MLN , P12872 ), a 22 amino-acid peptide derived from a precursor ( MLN , P12872 ), which may also generate a motilin-associated peptide ( MLN , P12872 ). There are significant species differences in the structure of motilin and its receptor, and in the functions of motilin. In humans and large mammals such as dog, activation of these receptors by motilin released from endocrine cells in the duodenal mucosa during fasting, induces propulsive phase III movements. This activity is associated with promoting hunger in humans. In humans and other mammals drugs and other non-peptide compounds which activate the motilin receptor may generate a more long-lasting ability to increase cholinergic activity within the upper gut, to promote upper gastrointestinal motility; this activity is suggested to be responsible for the gastrointestinal prokinetic effects of certain macrolide antibacterials (often called motilides; e.g. erythromycin, azithromycin), although for many of these molecules the evidence is sparse. Relatively high doses may induce vomiting and in humans, nausea. In terms of structure, the motilin receptor has closest homology with the ghrelin receptor. Thus, the human motilin receptor shares 52% overall amino acid identity with the human ghrelin receptor and 86% in the transmembrane regions [ 1084 , 2764 , 2814 ]. However, differences between the N-terminus regions of these receptors means that their cognate peptide ligands do not readily activate each other [ 579 , 2474 ]. Where studied the motilin receptor does not appear to have constitutive activity [ 1153 ]. Although not proven, the existence of biased agonism at the receptor has been suggested [ 1843 , 1918 , 2471 ]. A truncated 5-transmembrane structure has been identified but this is without activity when transfected into a host cell [ 5 ]. Receptor dimerisation has not been reported. It must be noted that for the complex macrolide structures, selectivity of action has often not been rigorously examined and other actions are possible ( e.g. P2X inhibition by erythromycin; [ 3246 ]). Small molecule and selective motilin receptor agonists are now described [ 1648 , 2474 , 3054 ]. Significant species-dependent variations exist. Among mammals, the gene encoding the motilin percursor is absent in laboratory rodents, while the receptor appears to be a pseudogene [ 1084 , 2472 ]. Functions of motilin are not usually detected in rodents, although brain and other responses to motilin and macrolides continue to be reported and the mechanism of these actions is obscure. In some non-laboratory rodents ( e.g . North American kangaroo rat ( Dipodomys ) and mouse ( Microdipodops ) a functional form of motilin may exist but the motilin receptor is non-functional [ 1648 ]. Marked differences in ligand affinities for the motilin receptor in dogs and humans may be explained by significant differences in receptor structure [ 2473 ]. Among birds, chicken ( Gallus gallus domesticus ) motilin differs from human motilin at positions 4, 7–10, and 12, and contracts avian upper gastrointestinal tissues more potently than human motilin; in rabbit duodenum, the reverse is apparent [ 1436 ]. Chicken motilin receptor has 59% sequence homology with the human motilin receptor [ 3144 ]. In chicken, motilin does not mediate phase III activity of the gastric MMC but initiates rhythmic oscillating complexes in the small intestine [ 2407 ]. Responsiveness to motilin in the ileum is highest in avian gastrointestinal tract. Among reptiles, caiman/alligator motilin is similar to avian motilin, but markedly different forms of motilin exist in turtles, anole/lizard and snake. Their activities have not been examined in reptiles. Among amphibians, a motilin-like peptide has been identified in newts but not in frogs, with a structure differing from mammalian motilin. There may be some diversity among the anuran, urodelal and gymnophional species. Although endogenous motilin is not present in frogs, human motilin caused contraction of the upper gastrointestinal tract [ 3235 ]. However, newt but not human motilin caused strong contraction of the stomach of Japanese fire belly newts [ 3234 ]. Among teleost fish, sequences for motilin peptide and motilin receptor have been identified (zebrafish, ballan wrasse, spotted sea bass) but the motilin peptides are short and the structure of motilin receptor differs from that of mammals. Zebrafish motilin activates its cognate motilin receptor but fails to cause contraction of gastrointestinal strips in vitro , perhaps because of low expression of the motilin receptor [ 1437 ].

Odorant receptors are also seven-transmembrane spanning G protein-coupled receptors, responsible for the detection of odorant, generally volatile compounds associated with olfaction. These are not currently included as they are not yet associated with extensive pharmacological data but are curated in the following databases: The gene list of odorant receptors at HGNC , and curated by HORDE and ORDB .

G protein-coupled receptors → Relaxin family peptide receptors Relaxin family peptide receptors (RXFP, nomenclature as agreed by the NC-IUPHAR Subcommittee on Relaxin family peptide receptors [ 160 , 1021 ]) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are heterodimeric peptide hormones structurally related to insulin: relaxin-1 ( RLN1 , P04808 ), relaxin ( RLN2 , P04090 ), relaxin-3 ( RLN3 , Q8WXF3 ) (also known as INSL7), insulin-like peptide 3 ( INSL3 ( INSL3 , P51460 )) and INSL5 ( INSL5 , Q9Y5Q6 ). Species homologues of relaxin have distinct pharmacology and relaxin ( RLN2 , P04090 ) interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 [ 2544 ]. Relaxin-3 ( RLN3 , Q8WXF3 ) is the ligand for RXFP3 but it also binds to RXFP1 and RXFP4 and has differential affinity for RXFP2 between species [ 2543 ]. INSL5 ( INSL5 , Q9Y5Q6 ) is the ligand for RXFP4 but is a weak antagonist of RXFP3. Relaxin ( RLN2 , P04090) and INSL3 ( INSL3 , P51460 ) have multiple complex binding interactions with RXFP1 [ 2562 ] and RXFP2 [ 1139 ], which together with the N-terminal linker and LDLa module drive receptor activation by an unknown mechanism [ 730 , 2545 ]. INSL5 ( INSL5 , Q9Y5Q6 ) and relaxin-3 ( RLN3 , Q8WXF3 ) interact with their receptors using distinct residues in their B-chains for binding, and activation, respectively [ 453 , 454 , 1186 , 3089 ]. Relaxin ( RLN2 , P04090 ) is the cognate peptide ligand for RXFP1. It has potent vasodilatory, anti-fibrotic, angiogenic, anti-apoptotic and anti-inflammatory effects which has led to the use of RXFP1 agonists for the treatment of acute heart failure (AHF) [ 680 ]. There are numerous long-acting RXFP1 agonists in clinical development for AHF, including small molecule agonist AZD5462 [ 962 ]], relaxin fusion peptide SE301 [ 731 ] and a relaxin peptidomimetic R2R01 [ 2259 ]. The antifibrotic actions of relaxin are dependent on the angiotensin receptor AT 2 [ 487 ] and are blocked by either AT 1 or AT 2 receptor antagonists [ 488 ]. INSL3 ( INSL3 , P51460 ) is the cognate peptide for RXFP2 and is a circulating hormone that in males is essential for testicular descent in utero [ 2043 ] and in females has important roles in ovarian follicle function [ 1244 ]. In adults, INSL3 has potential roles in testicular function [ 1245 ] and the musculo-skeletal system [ 607 ]. RXFP2 is also present in brain, associated with cortico-thalamic motor circuits [ 2551 ]. cAMP elevation is the major signalling pathway for both RXFP1 and RXFP2 [ 1183 , 1184 ], but RXFP1 also activates MAP kinases, nitric oxide signalling, and tyrosine kinase phosphorylation; and relaxin can interact with the glucocorticoid receptor [ 1023 ]. RXFP1 displays ultra-sensitive responses to sub picomolar levels of relaxin [ 510 ]. relaxin-3 ( RLN3 , Q8WXF3 ) is the cognate ligand for RXFP3 but also has high affinity for RXFP4, whereas INSL5 ( INSL5 , Q9Y5Q6 ) is the cognate ligand for RXFP4 and is a weak antagonist at RXFP3. Receptor expression profiles suggest that RXFP3 is a brain neuropeptide receptor [ 1763 , 1764 , 2640 ] and RXFP4 a gut hormone receptor [ 768 , 845 , 1473 ]. The brain relaxin-3/RXFP3 system modulates feeding [ 844 , 845 , 1066 , 2565 , 2639 ] via effects in the hypothalamus [ 597 , 844 , 1342 , 1343 ], anxiety [ 1831 , 2447 , 2451 , 3219 ], reward and motivated, goal-directed behaviours [ 1167 , 2447 , 2973 ], and spatial, social and fear memory [ 40 , 1015 , 1016 , 2036 ]. Furthermore, RXFP3 activation in the brainstem, nucleus of the solitary tract, modulates respiration at baseline and during reflex behaviour [ 832 ]. INSL5 is secreted from colonic and rectal enteroendocrine L cells, while RXFP4 is expressed by colonic 5-hydroxytryptamine (5-HT)-producing enterochromaffin cells [ 768 , 1473 ], consistent with actions of RXFP4 agonists on colon motility [ 656 ]. The INSL5/RXFP4 system has also been reported to affect food intake [ 980 ] and glucose homeostasis [ 1752 ]. RXFP3 and RXFP4 couple to G i/o and inhibit adenylyl cyclase [ 1704 , 2911 ], and also cause Erk1/2 phosphorylation [ 2911 ]. RXFP4 also causes phosphorylation of p38MAPK, Akt and S6RP [ 69 ] and GLP-1 secretion in vitro [ 68 ]. There is evidence that at RXFP3, relaxin ( RLN2 , P04090 ) is a biased ligand compared to the cognate ligand relaxin-3 ( RLN3 , Q8WXF3 ) [ 2911 ]. Single chain or two-chain peptide agonists and antagonists have been developed for RXFP3 [ 161 , 1065 , 1601 ] and RXFP4 [ 3101 , 3102 ]. The first small molecule agonist of these receptors, compound 4 [ 614 ] has nanomolar activity on both receptors. A subsequent lead optimization study resulted in compound 10d [ 988 ] which demonstrates higher specificity for RXFP3. The same group also developed a small molecule negative allosteric modulator of RXFP3, RLX-33 [ 874 ]. A specific RXFP3 small molecule agonist, WNN0109-C011 was discovered in a high throughput screening campaign [ 1680 ], while specific small molecule agonists for RXFP4, JK0621-D008 [ 1681 ] and DC591053 [ 453 ], have also been developed.

G protein-coupled receptors → Adhesion Class GPCRs Adhesion GPCRs are structurally identified on the basis of a large extracellular region, similar to the Class B GPCR, but which is linked to the 7TM region by a GPCR autoproteolysis-inducing (GAIN) domain [ 74 ] containing a GPCR proteolysis site (GPS). The N-terminal extracellular region often shares structural homology with adhesive domains (e.g. cadherins, immunolobulin, lectins) facilitating inter- and matricellular interactions and leading to the term adhesion GPCR [ 811 , 3193 ]. Several receptors have been suggested to function as mechanosensors [ 285 , 2229 , 2250 , 2525 , 3072 ]. Cryo-EM structures of the 7-transmembrane domain of several adhesion GPCRs have been determined recently [ 150 , 1683 , 2249 , 2250 , 2308 , 2313 , 3122 , 3268 ]. The nomenclature of these receptors was revised in 2015 as recommended by NC-IUPHAR and the Adhesion GPCR Consortium [ 1024 ].

G protein-coupled receptors → Bombesin receptors Mammalian bombesin (Bn) receptors comprise 3 subtypes: BB 1 , BB 2 , BB 3 ( nomenclature recommended by the NC-IUPHAR Subcommittee on bombesin receptors , [ 44 , 1280 ]). BB 1 and BB 2 are activated by the endogenous ligands neuromedin B ( NMB , P08949 ) (NMB), gastrin-releasing peptide ( GRP , P07492 ) (GRP), and GRP-(18–27) ( GRP , P07492 ). Bombesin is a tetra-decapeptide, originally derived from amphibians and structurally closely related to GRP. The three Bn receptor subtypes couple primarily to the G q/11 and G 12/13 family of G proteins [ 1280 ]. Each of these receptors is widely distributed in the CNS and peripheral tissues [ 48 , 936 , 1279 , 1280 , 1334 , 1955 , 2338 , 2477 , 3231 , 3251 ]. Activation of BB 1 and BB 2 receptors causes a wide range of physiological/pathophysiogical actions, including the stimulation of normal and neoplastic tissue growth, smooth-muscle contraction, respiration, gastrointestinal motility, feeding behavior, secretion and many central nervous system effects including regulation of circadian rhythm, body temperature control, sighing, behavioral disorders and mediation of pruritus [ 43 , 458 , 564 , 1280 , 1955 , 1964 , 1966 , 1966 , 2338 , 3251 ]. BB 3 is an orphan receptor, although some propose it is constitutively active [ 2786 ]. BB 3 receptor knockout studies show it has important roles in glucose and insulin regulation, metabolic homeostasis, feeding, regulation of body temperature, obesity, diabetes mellitus and growth of normal/neoplastic tissues [ 43 , 936 , 1650 , 1962 , 1962 , 2114 ]. Bn receptors are one of the most frequently overexpressed receptors in cancers and are receiving increased attention for their roles in tumor growth, as well as for tumour imaging and for receptor-targeted cytotoxicity especially for advanced prostate and breast cancer [ 164 , 1530 , 1787 , 1964 , 3226 , 3276 ]. Bn receptors are also receiving attention because they are one of the primary neurotransmitters for pruritus [ 458 , 1395 , 2206 ]. All three human subtypes may be activated by [D-Phe 6 ,β-Ala 11 ,Phe 13 ,Nle 14 ]bombesin-(6–14) [ 1810 , 2338 ]. A recent study [ 2336 ] shows that MK-5046 functions as an allosteric agonist for hBRS-3 (the first for any BnR). In a recent study the crystal structure of inactive hGRPR (BB 2 ) was reported, as well as two active state GRPR structures bound to GRP or [D-Phe6,β-Ala11,Phe13,Nle14]bombesin-(6–14) [ 2206 ]. An additional recent study [ 1644 ] reported the cryo-EM structures of BRS3 in complex with the heterotrimeric Gq protein in its active states: one bound to the pan-BnR agonist BA1 and the other bound to the synthetic BRS3-specific agonist MK-5046.

G protein-coupled receptors → Chemerin receptors Nomenclature for the chemerin receptors is presented as recommended by NC-IUPHAR [ 586 , 1375 ]). The chemoattractant protein and adipokine, chemerin ( RARRES2 , Q99969 ), has been shown to be the endogenous ligand for both chemerin family receptors. Chemerin 1 was the founding family member, and when GPR1 was de-orphanised it was re-named Chermerin 2 [ 1375 ]. Chemerin 1 is also activated by the lipid-derived, anti-inflammatory ligand resolvin E1 (RvE1), which is formed via the sequential metabolism of EPA by aspirin-modified cyclooxygenase and lipoxygenase [ 82 , 83 ]. In addition, two GPCRs for resolvin D1 (RvD1) have been identified: FPR2 and GPR32 , an orphan receptor [ 1500 ]. CCX832 (structure not disclosed) is a selective antagonist, p K i =9.2 [ 1377 ]. G protein-coupled receptors → Chemokine receptors Chemokine receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Chemokine Receptors [ 116 , 465 , 2004 , 2005 ]) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Additional hematopoietic and non-hematopoietic roles have been identified for many chemokines in the areas of embryonic development, immune cell proliferation, activation and death, viral infection, and as antibacterials, among others. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and “Atypical chemokine receptors”, which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients [ 116 ]. Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-chemokines; n = 28), CXC (also known as α-chemokines; n = 17) and CX3C ( n = 1) chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C chemokines ( n = 2) have only the second and fourth cysteines found in other chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most chemokine receptors are able to bind multiple high-affinity chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most chemokines bind to more than one receptor subtype. Receptors for inflammatory chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled chemokine receptors are named acccording to the class of chemokines bound, whereas ACKR is the root acronym for atypical chemokine receptors [ 117 , 465 ]. There can be substantial cross-species differences in the sequences of both chemokines and chemokine receptors, and in the pharmacology and biology of chemokine receptors. Endogenous and microbial non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard chemokine receptor names [ 3273 ] and aliases. Specific chemokine receptors facilitate cell entry by microbes, such as ACKR1 for Plasmodium vivax , and CCR5 and CXCR4 for HIV-1. Virally encoded chemokine receptors are known ( e.g. US28, a homologue of CCR1 from human cytomegalovirus and ORF74, which encodes a homolog of CXCR2 in Herpesvirus saimiri and gamma-Herpesvirus-68), but their role in viral life cycles is not established. Viruses can exploit or subvert the chemokine system by producing chemokine antagonists and scavengers. Three chemokine receptor antagonists have now been approved by the FDA: 1) the CCR5 antagonist maraviroc (Pfizer) for treatment of HIV/AIDS in patients with CCR5-using strains; and 2) the CXCR4 antagonist plerixafor (Sanofi) for hematopoietic stem cell mobilization with G-CSF ( CSF3 , P09919 ) in patients undergoing transplantation in the context of chemotherapy for Hodgkins’ Disease and multiple myeloma; and 3) the CCR4 blocking antibody Poteligeo ( mogamulizumab -kpkc, Kyowa Kirin, Inc.) for mycosis fungoides or Sezary syndrome; and the CXCR4 antagonist mavorixafor for WHIM syndrome.

G protein-coupled receptors → Dopamine receptors Dopamine receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Dopamine Receptors [ 2534 ]) are commonly divided into D 1 -like (D 1 and D 5 ) and D 2 -like (D 2 , D 3 and D 4 ) families, where the endogenous agonist is dopamine . The selectivity of many of these agents is less than two orders of magnitude. [ 3 H]raclopride exhibits similar high affinity for D 2 and D 3 receptors (low affinity for D 4 ), but has been used to label D 2 receptors in the presence of a D 3 -selective antagonist. [ 3 H]7-OH-DPAT has similar affinity for D 2 and D 3 receptors, but labels only D 3 receptors in the absence of divalent cations. The pharmacological profile of the D 5 receptor is similar to, yet distinct from, that of the D 1 receptor. The splice variants of the D 2 receptor are commonly termed D 2S and D 2L (short and long). The DRD4 gene encoding the D 4 receptor is highly polymorphic in humans, with allelic variations of the protein from amino acid 387 to 515.

G protein-coupled receptors → Glucagon receptor family The glucagon family of receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on the Glucagon receptor family [ 1850 ]) are activated by the endogenous peptide (27–44 aa) hormones glucagon ( GCG , P01275 ), glucagon-like peptide 1 ( GCG , P01275 ), glucagon-like peptide 2 ( GCG , P01275 ), glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory polypeptide ( GIP , P09681 )), GHRH ( GHRH , P01286 ) and secretin ( SCT , P09683 ). One common precursor ( GCG ) generates glucagon ( GCG , P01275 ), glucagon-like peptide 1 ( GCG , P01275 ) and glucagon-like peptide 2 ( GCG , P01275 ) peptides [ 1233 ]. For a recent review on the current understanding of the structures of GLP-1 and GLP-1R, the molecular basis of their interaction, and the associated signaling events see de Graaf et al ., 2016 [ 960 ]. The glucagon receptor has been reported to interact with receptor activity modifying proteins (RAMPs), specifically RAMP2 , in heterologous expression systems [ 496 ], although the physiological significance of this has yet to be established.

Potencies of agonists and antagonists listed in the table, quantified as IC 50 values for the inhibition of [ 3 H]CGP27492 binding to rat cerebral cortex membranes, are from [ 280 , 821 , 822 ]. Radioligand K D values relate to binding to rat brain membranes. CGP 71872 is a photoaffinity ligand for the GABA B1 subunit [ 188 ]. CGP27492 ( 3-APPA ), CGP35024 ( 3-APMPA ) and CGP44532 act as antagonists at human GABA A ρ1 receptors, with potencies in the low micromolar range [ 821 ]. In addition to the ligands listed in the table, Ca 2+ binds to the VTM of the GABA B1 subunit to act as a positive allosteric modulator of GABA [ 842 ]. Synthetic positive allosteric modulators with low, or no, intrinsic activity include CGP7930 , GS39783 , BHF-177 [ 2953 ] and (+)-BHFF [ 13 , 213 , 223 , 821 ]. The site of action of CGP7930 and GS39783 appears to be on the heptahelical domain of the GABA B2 subunit [ 697 , 2246 ]. In the presence of CGP7930 or GS39783 , CGP35348 and 2-hydroxy-saclofen behave as partial agonists [ 821 ]. A negative allosteric modulator of GABA B activity has been reported [ 442 ]. Knock-out of the GABA B1 subunit in C57B mice causes the development of severe tonic-clonic convulsions that prove fatal within a month of birth, whereas GABA B1 −/− BALB/c mice, although also displaying spontaneous epileptiform activity, are viable. The phenotype of the latter animals additionally includes hyperalgesia, hyperlocomotion (in a novel, but not familiar, environment), hyperdopaminergia, memory impairment and behaviours indicative of anxiety [ 726 , 2901 ]. A similar phenotype has been found for GABA B2 −/− BALB/c mice [ 868 ].

G protein-coupled receptors → Adenosine receptors Adenosine receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [ 809 ]) are activated by the endogenous ligand adenosine (potentially inosine also at A 3 receptors). Crystal and cryo-EM structures for all four adenosine receptors have been solved, occupied by either agonists (sometimes in the presence of an allosteric modulator) or antagonists. Many of these structures were incorporated in a recent review [ 1219 ]. More recently, structures for the A 2B receptor [ 360 , 452 ] and the A 3 receptor [ 359 , 2144 ] were elucidated. The A 2A receptor is used as a workhorse in GPCR structure elucidation: almost 100 structures are available in the Protein Data Bank ( www.rcsb.org ). Istradefylline , a selective A 2A receptor antagonist, is on the market for the treatment of Parkinson’s disease, while caffeine’s mechanism of action is largely due to its antagonism of at least three of the four adenosine receptor subtypes. Allosteric modulators, particular PAMs of A 1 and A 3 receptors, have been explored chemically and structurally [ 678 , 2279 ]. Adenosine inhibits many intracellular ATP-utilising enzymes, including adenylyl cyclase (P-site). A pseudogene exists for the A 2B adenosine receptor ( ADORA2BP1 ) with 79% identity to the A 2B adenosine receptor cDNA coding sequence, but which is unable to encode a functional receptor [ 1258 ]. DPCPX also exhibits antagonism at A 2B receptors (p K i ca. 7,[ 45 , 1445 ]). Antagonists at A 3 receptors exhibit marked species differences, such that only MRS1523 and MRS1191 are selective at the rat A 3 receptor. In the absence of other adenosine receptors, [ 3 H]DPCPX and [ 3 H]ZM 241385 can also be used to label A 2B receptors (K D ca . 30 and 60 nM respectively). [ 125 I]AB-MECA also binds to A 1 receptors [ 1445 ]. [ 3 H]CGS 21680 is relatively selective for A 2A receptors, but may also bind to other sites in cerebral cortex [ 565 , 1297 ]. [ 3 H]NECA binds to other non-receptor elements, which also recognise adenosine [ 1734 ].

G protein-coupled receptors → Histamine receptors Histamine receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Histamine Receptors [ 1125 , 2168 ]) are activated by the endogenous ligand histamine . Marked species differences exist between histamine receptor orthologues [ 1125 ]. The human and rat H 3 receptor genes are subject to significant splice variance [ 134 ]. The potency order of histamine at histamine receptor subtypes is H 3 = H 4 > H 2 > H 1 [ 2168 ]. Some agonists at the human H 3 receptor display significant ligand bias [ 2389 ]. Antagonists of all 4 histamine receptors have clinical uses: H 1 antagonists for allergies ( e.g. cetirizine ), H 2 antagonists for acid-reflux diseases ( e.g. ranitidine ), H 3 antagonists for narcolepsy ( e.g. pitolisant/WAKIX ; Registered) and H 4 antagonists for atopic dermatitis ( e.g. adriforant ; Phase IIa) [ 2168 ] and vestibular neuritis (AUV) (SENS-111 (Seliforant, previously UR-63325), entered and completed vestibular neuritis (AUV) Phase IIa efficacy and safety trials, respectively) [ 95 , 2937 ]. Histamine receptor photopharmacology has provided both agonist and antagonist tools to achieve optical control over H 3 receptor function. The best-characterized agonist is VUF15000 , an azobenzene-containing compound in which the trans-isomer binds the H 3 receptor with nanomolar affinity (K i = 4 nM) and behaves as a full agonist. Its cis-isomer is approximately 10-fold less active, thereby creating a reversible light-controlled switch for receptor activation that has been validated in binding, NanoBRET biosensor, and electrophysiology assays [ 1070 ]. Also several photoswitchable antagonists have been established as tools for histamine H 3 receptor photopharmacology. The first-generation azobenzene-based antagonists included VUF14738 and VUF14862 , which are part of a bidirectional toolbox [ 1069 ]. VUF14738 (trans: K i = 631 nM) shows a light-induced 10-fold increase in affinity, while VUF14862 (trans: K i = 1.6 nM) displays the opposite, with more than a tenfold change upon illumination. Both compounds are highly fatigue-resistant, underwent rapid trans-cis isomerization, and had long thermal half-lives, allowing reversible optical control in binding and electrophysiological assays. Building on these scaffolds, recently 2nd generation ligands were developed to overcome limitations of azobenzenes [ 224 ]. The arylazopyrazole-based antagonist VUF26063 displayed subnanomolar affinity at the H 3 receptor in its trans isomer (K i = 0.5 nM) and a 50-fold lower affinity in the cis state. This compound showed robust switching with high photostationary state efficiency and improved aqueous solubility compared to earlier analogues. Importantly, radiolabeling yielded [ 3 H]VUF26063, the first radiolabeled photoswitchable GPCR ligand, enabling the direct study of ligand binding kinetics and photoisomerization inside the receptor pocket in real time. These antagonists, together with the agonist VUF15000 , provide a well-characterized toolkit of photosensitive ligands that can be used to dissect H 3 receptor pharmacology with spatiotemporal precision. Histaprodifen and methylhistaprodifen are reduced efficacy agonists. The H 4 receptor appears to exhibit broadly similar pharmacology to the H 3 receptor for imidazole-containing ligands, although ( R )-α-methylhistamine and N -α-methylhistamine are less potent, while clobenpropit acts as a reduced efficacy agonist at the H 4 receptor and an antagonist at the H 3 receptor [ 1706 , 2022 , 2067 , 2106 , 3269 ]. Moreover, 4-methylhistamine is identified as a high affinity, full agonist for the human H 4 receptor [ 1676 ]. [ 3 H]histamine has been used to label the H 4 receptor in heterologous expression systems.

G protein-coupled receptors → Melatonin receptors Melatonin receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Melatonin Receptors [ 687 ]) are activated by the endogenous ligands melatonin and clinically used drugs like ramelteon , agomelatine and tasimelteon . Melatonin , 2-iodo-melatonin , agomelatine , GR 196429 , LY 156735 and ramelteon [ 1355 ] are nonselective agonists for MT 1 and MT 2 receptors. (−)-AMMTC displays an ~400-fold greater agonist potency than (+)-AMMTC at rat MT 1 receptors (see AMMTC for structure) [ 2835 ]. Luzindole is an MT 1 /MT 2 non-selective competitive melatonin receptor antagonist with about 15–25 fold selectivity for the MT 2 receptor [ 689 ]. MT 1 /MT 2 heterodimers present different pharmacological profiles from MT 1 and MT 2 receptors [ 111 ]. The MT 3 binding site of hamster brain and peripheral tissues such as kidney and testis, also termed the ML 2 receptor, binds selectively 2-iodo-[ 125 I]5MCA-NAT [ 1937 ]. Pharmacological investigations of MT 3 binding sites have primarily been conducted in hamster tissues. At this site, The endogenous ligand N-acetylserotonin [ 710 , 1741 , 1937 , 2261 ] and 5MCA-NAT [ 2261 ] appear to function as agonists, while prazosin [ 1741 ] functions as an antagonist. The MT 3 binding site of hamster kidney was also identified as the hamster homologue of human quinone reductase 2 ( NQO2 , P16083 [ 2092 , 2093 ]). The MT 3 binding site activated by 5MCA-NAT in eye ciliary body is positively coupled to adenylyl cyclase and regulates chloride secretion [ 1197 ]. Xenopus melanophores and chick brain express a distinct receptor (x420, P49219 ; c346, P49288 , initially termed Mel 1C ) coupled to the G i/o family of G proteins, for which GPR50 has recently been suggested to be a mammalian counterpart [ 692 ] although melatonin does not bind to GPR50 receptors. Several variants of the MTNR1B gene have been associated with increased type 2 diabetes risk [ 1348 ].

G protein-coupled receptors → Succinate receptor Nomenclature as recommended by NC-IUPHAR [ 586 ]. The succinate receptor (GPR91, SUCNR1 ) is activated by the tricarboxylic acid (or Krebs) cycle intermediate succinate and other dicarboxylic acids with less clear physiological relevance such as maleate [ 1088 ]. Since its pairing with its endogenous ligand in 2004, intense research has focused on the receptor-ligand pair role in various (patho)physiological processes such as regulation of renin production [ 1088 , 2846 ], ischemia injury [ 1088 ], fibrosis [ 1768 ], retinal angiogenesis [ 2478 ], inflammation [ 1699 , 1768 ], immune response [ 2433 ], obesity [ 1369 , 1858 , 2946 ], diabetes [ 1652 , 2846 , 2912 ], platelet aggregation [ 2674 , 2790 ] or cancer [ 2322 , 3106 ]. The succinate receptor is coupled to G i/o [ 909 , 1088 ] and G q/11 protein families [ 1088 , 2404 , 2866 ], whilst coupling to these G proteins is dependent on the cellular, metabolic and spatial context [ 1668 , 2866 ]. Although the receptor is, upon ligand addition, rapidly desensitized [ 1146 , 2404 ], and in some cells internalized [ 1088 ], it seems to recruit arrestins weakly [ 901 ]. The cellular activation of the succinate receptor triggers various signalling pathways such as decrease of cAMP levels, [Ca 2+ ] i mobilization and activation of kinases (ERK, c-Jun, Akt, Src, p38, PI3Kβ, etc. ) [ 910 ]. The receptor is broadly expressed but is notably abundant in immune cells (M2 macrophages [ 1369 , 2866 ], monocytes [ 2433 ], immature dendritic cells [ 2433 ], adipocytes [ 2946 ], platelets [ 2674 , 2790 ], etc. ) and in the kidney [ 1088 ]. In humans, there is the possibility of two open-reading frames (ORFs) for SUCNR1 , one giving a protein of 330 amino acids (AA) and the other one 334-AA. Wittenberger et al. [ 3086 ] noted that the 330-AA protein was more likely to be expressed given the Kozak sequence surrounding the second ATG. Some databases report SUCNR1 as being 334-AA long.

G protein-coupled receptors → Urotensin receptor The urotensin-II (U-II) receptor (UT, nomenclature as agreed by the NC-IUPHAR Subcommittee on the Urotensin receptor [ 674 , 789 , 2935 ]) is activated by the endogenous dodecapeptide urotensin-II ( UTS2 , O95399 ), originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish [ 204 , 2934 ]. Several structural forms of U-II exist in fish and amphibians [ 2935 ]. The goby orthologue was used to identify U-II as the cognate ligand for the predicted receptor encoded by the rat gene gpr14 [ 58 , 547 , 1715 , 1969 , 2094 ]. Human urotensin-II ( UTS2 , O95399 ), an 11-amino-acid peptide [ 547 ], retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding [ 309 , 1425 , 1630 ]. This sequence is also conserved in the deduced amino-acid sequence of rat urotensin-II {Rat} (14 amino-acids) and mouse urotensin-II{Mouse} (14 amino-acids), although the N-terminal is more divergent from the human sequence [ 546 ]. A second endogenous ligand for the UT has been discovered in rat [ 2724 ]. This is the urotensin II-related peptide ( UTS2B , Q765I0 ), an octapeptide that is derived from a different gene, but shares the C-terminal sequence (CFWKYCV) common to U-II from other species. Identical sequences to rat urotensin II-related peptide ( UTS2B , Q765I0 ) are predicted for the mature mouse and human peptides [ 685 ]. UT exhibits relatively high sequence identity with somatostatin, opioid and galanin receptors [ 2935 ]. The urotensinergic system displays an unprecedented repertoire of four or five ancient UT in some vertebrate lineages and five U-II family peptides in teleost fish [ 2857 ]. In the human vasculature, human urotensin-II ( UTS2 , O95399 ) elicits both vasoconstrictor (p D 2 9.3–10.1, [ 1783 ]) and vasodilator (pIC 50 10.3–10.4, [ 2699 ]) responses.

G protein-coupled receptors → Bradykinin receptors Bradykinin (or kinin) receptors ( nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [ 1608 ]) are activated by the endogenous peptides bradykinin ( KNG1 , P01042 ) (BK), [des-Arg 9 ]bradykinin ( KNG1 , P01042 ), Lys-BK ( kallidin ( KNG1 , P01042 )), [des-Arg 10 ]kallidin ( KNG1 , P01042 ), [Phospho-Ser 6 ]-Bradykinin, T-kinin ( KNG1 , P01042 ) (Ile-Ser-BK), [Hyp 3 ]bradykinin ( KNG1 , P01042 ) and Lys-[Hyp 3 ]-bradykinin ( KNG1 , P01042 ). Variation in pharmacology and activity of B 1 and B 2 receptor antagonists at species orthologs has been documented. Icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema. Inhibition of bradykinin with icatibant in COVID-19 infection is under clinical evaluation, with trial NCT05407597 .

G protein-coupled receptors → Calcitonin receptors This receptor family comprises a group of receptors for the calcitonin/CGRP family of peptides. The calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors [ 1074 , 1076 , 2278 ]) are generated by the genes CALCR (which codes for the calcitonin receptor, CTR) and CAL-CRL (which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying proteins), which are single TM domain proteins of ca. 150 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of the CTR; these in turn produce variants of amylin receptors [ 2278 ], some of which can be potently activated by CGRP. The endogenous agonists are the peptides calcitonin ( CALCA , P01258 ), α-CGRP ( CALCA , P06881 ) (formerly known as CGRP-I), β-CGRP ( CALCB , P10092 ) (formerly known as CGRP-II), amylin ( IAPP , P10997 ) (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), adrenomedullin ( ADM , P35318 ) and adrenomedullin 2/intermedin ( ADM2 , Q7Z4H4 ). There are species differences in peptide sequences, particularly for the calcitonins. CTR-stimulating peptide {Pig} (CRSP) is another member of the family with selectivity for the CTR but it is not expressed in humans [ 1353 ]. CLR (calcitonin receptor-like receptor) by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, adrenomedullin and adrenomedullin 2/intermedin. There are several approved drugs that target this receptor family, such as pramlintide , erenumab , and the “gepant” class of CGRP receptor antagonists. There are also species differences in agonist pharmacology; for example, CGRP displays potent activity at multiple rat and mouse receptors [ 124 , 861 ]. The summary table only reflects human receptor pharmacology.

G protein-coupled receptors → Complement peptide receptors Complement peptide receptors ( nomenclature as agreed by the NC-IUPHAR subcommittee on Complement peptide receptors [ 1444 ]) are activated by the endogenous ~75 amino-acid anaphylatoxin polypeptides C3a ( C3 , P01024 ) and C5a ( C5 , P01031 ), generated upon stimulation of the complement cascade. C3a and C5a exert their functions through binding to their receptors (C3a receptor, C5a receptor 1 and C5a receptor 2), causing cell recruitment and triggering cellular degranulation that contributes to local inflammation. SB290157 has also been reported to have agonist properties at the C3a receptor [ 1657 , 1836 ]. JR14a, originally reported as an antagonist, has since been shown to exert full agonist activity [ 1406 ]. The chemoattractant receptor C5a 2 (also known as GPR77, C5L2) binds C5a and has putative roles in either opposing or promoting inflammatory responses [ 363 , 847 , 873 , 1658 , 2165 ]. Binding to this site may be displaced with the rank order C5a des-Arg ( C5 ) > C5a ( C5 , P01031 ) [ 363 , 2127 ] while there is controversy over the ability of C3a ( C3 , P01024 ) and C3a des Arg ( C3 , P01024 ) to compete [ 1158 , 1327 , 1328 , 2127 ]. C5a 2 appears to lack G protein signalling and has been termed a decoy receptor [ 2542 ]. However, C5a 2 does recruit β-arrestin 2 after ligand binding, which might provide a signalling pathway for this receptor [ 137 , 2914 ], and forms heteromers with C5a 1 . A recent study has identified p90RSK (90 kDa ribosomal s6 kinase) phosphorylation as a potential signalling pathway for C5a 2 [ 2163 ]. C5a, but not C5a-des Arg, induces upregulation of heterodimer formation between complement C5a receptors C5a 1 and C5a 2 [ 556 ]. There are also reports of pro-inflammatory activity of C5a 2 , mediated by HMGB1, likely through AKT and MAPK signalling pathways (reviewed in [ 1651 , 3238 ]). In T cells it has been shown that C5a 1 and C5a 2 act in opposition to each other and that altering the equilibrium between the two receptors, by differential expression or production of C5a-des Arg (which favours C5a 2 ), can affect the final cellular response [ 76 ]. In human macrophages, C5a 2 was observed to modulate multiple complement and chemokine receptor-mediated signalling and pattern recognition-induced cytokine responses, independent of C5a 1 [ 1656 ]. In addition, C5a 2 is reported to act as a C5a transporter on endothelial cells, and is required for the transport of C5a into the vessel lumen and the subsequent neutrophil arrest in arthritis [ 1924 ].

G protein-coupled receptors → Endothelin receptors Endothelin receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Endothelin Receptors [ 585 ]) are activated by the endogenous 21 amino-acid peptides endothelins 1–3 ( endothelin-1 ( EDN1 , P05305 ), endothelin-2 ( EDN2 , P20800 ) and endothelin-3 ( EDN3 , P14138 )). Splice variants of the ET A receptor have been identified in rat pituitary cells; one of these, ET A R-C13, appeared to show loss of function with comparable plasma membrane expression to wild type receptor [ 1063 ]. Subtypes of the ET B receptor have been proposed, although gene disruption studies in mice suggest that only a single gene product exists [ 1926 ]. Cryogenic-electron microscopy structures of ET A and ET B bound to endothelin-1 ( EDN1 , P05305 ) and ET B bound to sovateltide (IRL1620) [ 1286 ] and crystal structures of the ET B receptor complexed with non-selective agonists eendothelin-1 ( EDN1 , P05305 ) [ 2588 ] and sarafotoxin S6b [ 1248 ], ET B selective agonists endothelin-3 ( EDN3 , P14138 ) and sovateltide (IRL1620) [ 2587 ], inverse agonist IRL 2500 [ 2015 ], and clinically relevant non-selective antagonist bosentan and the ET B selective analogue K-8794 [ 2589 ] have been reported. Sparsentan is a combined ET A and AT 1 receptor antagonist [ 1487 ]. ET A -selective ( ambrisentan ) and mixed ET A /ET B ( bosentan , macitentan ) antagonists are approved for use in pulmonary arterial hypertension (PAH) [ 9 , 2576 ]. The mixed antagonist, aprocitentan has been approved for use in resistant hypertension [ 634 ]. Atrasentan , an ET A selective antagonist is approved for use in primary IgA nephropathy [ 1366 ] and the ET B selective agonist, sovateltide is approved for use in cerebral ischaemic stroke [ 1367 ].

G protein-coupled receptors → Kisspeptin receptor The kisspeptin receptor ( nomenclature as agreed by the NC-IUPHAR Subcommittee on the kisspeptin receptor [ 1428 ]), like neuropeptide FF (NPFF), prolactin-releasing peptide (PrP) and QRFP receptors (provisional nomenclature) responds to endogenous peptides with an arginine-phenylalanine-amide (RFamide) motif. Kisspeptin-54 ( KISS1 , Q15726 ) (KP54, originally named metastin), kisspeptin-13 ( KISS1 , Q15726 ) (KP13) and kisspeptin-10 ( KISS1 ) (KP10) are biologically-active peptides cleaved from the KISS1 ( Q15726 ) gene product. Kisspeptins have roles in, for example, cancer metastasis, fertility/puberty regulation and glucose homeostasis. 2-acylamino-4,6-diphenylpyridine derivatives have been described and are the first small molecule kisspeptin receptor antagonists reported with potential for treatment of sex-hormone dependent diseases such as prostate cancer and endometriosis [ 591 , 1452 ].

G protein-coupled receptors → Neuromedin U receptors Neuromedin U receptors ( provisional nomenclature as recommended by NC-IUPHAR [ 789 ]) are activated by the endogenous 25 amino acid peptide neuromedin U ( neuromedin U-25 ( NMU , P48645 ), NmU-25), a peptide originally isolated from pig spinal cord [ 1913 ]. In humans, NmU-25 appears to be the sole product of a precursor gene ( NMU , P48645 ) showing a broad tissue distribution, but which is expressed at highest levels in the upper gastrointestinal tract, CNS, bone marrow and fetal liver. Much shorter versions of NmU are found in some species, but not in human, and are derived at least in some instances from the proteolytic cleavage of the longer NmU. Despite species differences in NmU structure, the C-terminal region (particularly the C-terminal pentapeptide) is highly conserved and contains biological activity. Neuromedin S ( neuromedin S-33 ( NMS , Q5H8A3 )) has also been identified as an endogenous agonist [ 1968 ]. NmS-33 is, as its name suggests, a 33 amino-acid product of a precursor protein derived from a single gene and contains an amidated C-terminal heptapeptide identical to NmU. NmS-33 appears to activate NMU receptors with equivalent potency to NmU-25. NMU1 and NMU2 couple predominantly to G q/11 although there is evidence of good coupling to G i/o [ 304 , 1170 , 1182 ]. NMU1 and NMU2 can be labelled with [ 125 I]-NmU and [ 125 I]-NmS (of various species, e.g. [ 1877 ]), BODIPY ® TMR-NMU or Cy3B-NMU-8 [ 304 ]. A range of radiolabelled ( 125 I-), fluorescently labelled ( e.g. Cy3, Cy5, rhodamine and FAM) and biotin labelled versions of neuromedin U-25 ( NMU , P48645) and neuromedin S-33 ( NMS , Q5H8A3 ) are now commercially available.

G protein-coupled receptors → Prostanoid receptors Prostanoid receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Prostanoid Receptors [ 3095 ]) are activated by the endogenous ligands prostaglandins PGD 2 , PGE 1 , PGE 2 , PGF 2α , PGH 2 , prostacyclin [ PGI 2 ] and thromboxane A 2 . Differences and similarities between human and rodent prostanoid receptor orthologues, and their specific roles in pathophysiologic conditions are reviewed in [ 2091 ]. Measurement of the potency of PGI 2 and thromboxane A 2 is hampered by their instability in physiological salt solution; they are often replaced by cicaprost and U46619 , respectively, in receptor characterization studies. Whilst cicaprost is selective for IP receptors, it does exhibit moderate agonist potency at EP 4 receptors [ 10 ]. Apart from IP receptors, iloprost also binds to EP 1 receptors. The EP 1 agonist 17-phenyl-ω-trinor-PGE 2 also shows agonist activity at EP 3 and EP 4 receptors [ 798 , 2810 ]. Butaprost and SC46275 may require de-esterification within tissues to attain full agonist potency. There is evidence for subtypes of FP [ 1674 ] and TP receptors [ 1496 , 2358 ]. mRNA for the EP 3 receptor undergoes alternative splicing to produce variants which can interfere with signalling [ 2128 ] or generate complex patterns of G-protein (G i/o , G q/11 , G s and G 12,13 ) coupling ( e.g. [ 1482 , 2044 ]). The number of EP 3 receptor (protein) variants are variable depending on species. For the human prostaglandin EP 3 receptor, there exist five different EP 3 isoform proteins (EP 3 -I, EP 3 -II, EP 3 -III, EP 3 -IV and EP 3 -e). Three isoforms exist in rat and mouse. Putative receptor(s) for prostamide F (which as yet lack molecular correlates) and which preferentially recognize PGF2–1-ethanolamide and its analogues ( e.g . Bimatoprost ) have been identified, together with moderate-potency antagonists ( e.g. AGN 211334 ) [ 3094 ]. The free acid form of AL-12182, AL12180, used in in vitro studies, has a EC 50 of 15nM which is the concentration of the compound giving half-maximal stimulation of inositol phosphate turnover in HEK-293 cells expressing the human FP receptor [ 2574 ]. References given alongside the TP receptor agonists I-BOP [ 1849 ] and STA 2 [ 85 ] use human platelets as the source of TP receptors for competition radio-ligand binding assays to determine the indicated activity values. Pharmacological evidence for a second IP receptor, denoted IP 2 , in the central nervous system [ 2773 , 3027 ] and in the BEAS-2B human airway epithelial cell line [ 3080 ] is available. This receptor is selectively activated by 15R-17,18,19,20-tetranor-16-m-tolyl-isocarbacyclin ( 15R-TIC ) and 15R-deoxy 17,18,19,20-tetranor-16-m-tolyl-isocarbacyclin ( 15-deoxy-TIC ). However, molecular biological evidence for an IP 2 subtype is currently lacking. The IP antagonist CAY10441 also exhibits affinity for some alpha adrenoceptors (rat/human pK i 5.9–6.5) [ 236 ].

G protein-coupled receptors → Tachykinin receptors Tachykinin receptors ( provisional nomenclature as recommended by NC-IUPHAR [ 789 ]) are activated by the endogenous peptides substance P ( TAC1 , P20366 ) (SP), neurokinin A ( TAC1 , P20366 ) (NKA; previously known as substance K, neurokinin α, neuromedin L), neurokinin B ( TAC3 , Q9UHF0 ) (NKB; previously known as neurokinin β, neuromedin K), neuropeptide K ( TAC1 , P20366 ) and neuropeptide γ ( TAC1 , P20366 ) (N-terminally extended forms of neurokinin A). The neurokinins (A and B) are mammalian members of the tachykinin family, which includes peptides of mammalian and nonmammalian origin containing the consensus sequence: Phe-x-Gly-Leu-Met. Marked species differences in in vitro pharmacology exist for all three receptors, in the context of nonpeptide ligands. Antagonists such as aprepitant and fosaprepitant were approved by FDA and EMA, in combination with other antiemetic agents, for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy. The NK 1 receptor has also been described to couple to G proteins other than G q/11 [ 2427 ]. The crystal structure of the human NK 1 receptor in complex with antagonists has been determined [ 2526 , 3186 ]. The hexapeptide agonist septide appears to bind to an overlapping but non-identical site to substance P ( TAC1 , P20366 ) on the NK 1 receptor. There are additional subtypes of tachykinin receptor; an orphan receptor (SwissProt P30098 ) with structural similarities to the NK 3 receptor was found to respond to NKB when expressed in Xenopus oocytes or Chinese hamster ovary cells [ 664 , 1495 ]. NK 1 receptor antagonists affect cellular physiology including inflammation, apoptosis and cell trafficking and have a role in therapeutics [ 1999 , 2677 ].

G protein-coupled receptors → Angiotensin receptors The actions of angiotensin II ( AGT , P01019 ) (Ang II) are mediated by AT 1 and AT 2 receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Angiotensin receptors [ 599 , 1350 ]), which have around 30% sequence similarity. The octapeptide angiotensin II ( AGT , P01019 ) and the heptapeptide angiotensin III ( AGT , P01019 ) are endogenous ligands. The “sartan” family drugs such as losartan , candesartan , olmesartan , telmisartan , etc. are clinically used AT 1 receptor blockers. AT 1 receptors are predominantly coupled to G q/11 [ 599 , 1350 , 3223 ], however they also recruit β-arrestins and stimulate G protein-independent β-arrestin signaling [ 1271 , 1755 , 3213 ]. Most species express a single AGTR1 gene located on chromosome 3, but two related Agtr1a and Agtr1b receptor genes are expressed in rodents. Expression of the X chromosome-linked AGTR2 gene is higher in females than males [ 2468 ]. AT 1 receptor antagonists bearing substituted biphenyl tetrazolium moieties are clinically used to treat hypertension and other cardiovascular disorders. They bind to AT 1 receptors with nanomolar affinity and are more potent than losartan in functional studies [ 1350 ]. High-resolution crystal structures of AT 1 receptor bound to non-peptide antagonists (PDB id: 4ZUD, 4YAY), peptide agonists (PDB id: 6DO1, 6OS0, 6OS1, 6OS2) and G protein G q (7F6G) are deposited in the protein structure database [ 2620 , 3223 ]. Structural details of nanobodies (PDB id: 8TH4, 9EAH, 9EAI, 9EAJ) acting as AT 1 receptor antagonists are reported [ 2626 , 2627 ]. The AT 1 and bradykinin B2 receptors have been proposed to form a heterodimeric complex [ 3 ]. β-arrestin1 prevents AT 1 -B2 receptor heteromerization [ 2320 ]. The AT 2 receptor counteracts several of the growth responses initiated by AT 1 receptors. The AT 2 receptor is much less abundant than the AT 1 receptor in adult tissues and is upregulated in pathological conditions. Agonist activation of AT 2 receptors promotes anti-fibrotic tissue protection in cardiovascular and renal diseases [ 3012 ]. AT 2 receptors are involved in pain modulation [ 63 , 2383 ] and AT 2 receptor antagonists relieve peripheral neuropathic pain in chronic diseases such as diabetes [ 2383 , 2647 ]. High-resolution structures of the AT 2 receptor bound to non-peptide antagonists (PDB id: 5UNF, 7JNI) and peptide agonists (PDB id: 5XJM, 6JOD) are available in the protein structure database [ 2620 ]. An AT 3 receptor was proposed based on cDNA isolated from a neuroblastoma cell line, but existence of a genuine AGTR3 gene and AT 3 receptor are not confirmed at this time. However, there is evidence for an AT 4 receptor that specifically binds angiotensin IV ( AGT , P01019 ) ( AGT ; P01019 ) and is located in the brain and kidney. An additional putative endogenous ligand for the AT 4 receptor has been described ( LVV-hemorphin ( HBB , P68871 ) [ HBB , P68871 ], a globin decapeptide) [ 1930 ].

G protein-coupled receptors → Cannabinoid receptors Cannabinoid receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Cannabinoid Receptors [ 2223 ]) are activated by endogenous ligands that include N-arachidonoylethanolamine ( anandamide ), N-homo-γ-linolenoylethanolamine , N-docosatetra-7,10,13,16-enoylethanolamine and 2-arachidonoylglycerol . Potency determinations of endogenous agonists at these receptors are complicated by the possibility of differential susceptibility of endogenous ligands to enzymatic conversion [ 46 ]. There are currently three licenced cannabinoid medicines each of which contains a compound that can activate CB 1 and CB 2 receptors [ 2221 ]. Two of these medicines were developed to suppress nausea and vomiting produced by chemotherapy. These are nabilone (Cesamet ® ), a synthetic CB 1 /CB 2 receptor agonist, and synthetic Δ 9 -tetrahydrocannabinol (Marinol ® ; dronabinol), which can also be used as an appetite stimulant. The third medicine, Sativex ® , contains mainly Δ 9 -tetrahydrocannabinol and cannabidiol , both extracted from cannabis, and is used to treat multiple sclerosis and cancer pain. Both CB 1 and CB 2 receptors may be labelled with [ 3 H]CP55940 (0.5 nM; [ 2604 ]) and [ 3 H]WIN55212–2 (2–2.4 nM; [ 2636 , 2666 ]). Anandamide is also an agonist at vanilloid receptors ( TRPV1 ) and PPARs [ 2102 , 3279 ]. There is evidence for an allosteric site on the CB 1 receptor [ 2282 ]. All of the compounds listed as antagonists behave as inverse agonists in some bioassay systems [ 2223 ]. For some cannabinoid receptor ligands, additional pharmacological targets that include GPR55 and GPR119 have been identified [ 2223 ]. Moreover, GPR18 , GPR55 and GPR119 , although showing little structural similarity to CB 1 and CB 2 receptors, respond to endogenous agents that are structurally similar to the endogenous cannabinoid ligands [ 2223 ].

G protein-coupled receptors → Leukotriene receptors The leukotriene receptors ( nomenclature as agreed by the NC-IUPHAR subcommittee on Leukotriene Receptors [ 118 , 119 ]) are activated by the endogenous ligands leukotrienes (LT), synthesized from lipoxygenase metabolism of arachidonic acid. The human BLT1 receptor is the high affinity LTB 4 receptor whereas the BLT2 receptor in addition to being a low-affinity LTB 4 receptor also binds several other lipoxygenase-products, such as 12S-HETE , 12S-HPETE , 15S-HETE , and the thromboxane synthase product 12-hydroxyheptadecatrienoic acid . The BLT receptors mediate chemotaxis and immunomodulation in several leukocyte populations and are in addition expressed on non-myeloid cells, such as vascular smooth muscle and endothelial cells. In addition to BLT receptors, LTB 4 has been reported to bind to the peroxisome proliferator activated receptor (PPAR) α [ 1686 ] and the vanilloid TRPV1 ligand-gated nonselective cation channel [ 1863 ]. The crystal structure of the BLT1 receptor was initially determined in complex with selective antagonists [ 1164 , 1891 ] and extended to the cryo-electron microscopy structure of LTB 4 -bound human BLT1 receptor at 2.91 Å resolution [ 3002 ]. The receptors for the cysteinyl-leukotrienes ( i.e. LTC 4 , LTD 4 and LTE 4 ) are termed CysLT1 and CysLT2 and exhibit distinct expression patterns in human tissues, mediating for example smooth muscle cell contraction, regulation of vascular permeability, and leukocyte activation. The crystal structures of both receptors have been solved; CysLT1 in complex with zafirlukast and pranlukast [ 1742 ] and CysLT2 in complex with three dual CysLT1/CysLT2 antagonists [ 1006 ]. There is also evidence in the literature for additional CysLT receptor subtypes, derived from functional in vitro studies, radioligand binding and in mice lacking both CysLT1 and CysLT2 receptors [ 119 ]. Cysteinyl-leukotrienes have also been suggested to signal through the P2Y12 receptor [ 810 , 2090 , 2174 ], GPR17 [ 506 ] and the oxoglutarate receptor OXGR1 (previously referred to as GPR99) [ 1336 ]. The FPR2 receptor ( nomenclature as agreed by the NC-IUPHAR subcommittee on Leukotriene and Lipoxin Receptors [ 119 ]) is activated by the endogenous lipid-derived, anti-inflammatory ligands lipoxin A 4 ( LXA 4 ) and 15-epi-LXA 4 ( aspirin triggered lipoxin A4 , ATL). The FPR2/ALX receptor also interacts with endogenous peptide and protein ligands, such as MHC binding peptide [ 469 ] as well as annexin I ( ANXA1 , P04083 ) (ANXA1) and its N -terminal peptides [ 535 , 2216 ]. In addition, a soluble hydrolytic product of protease action on the urokinase-type plasminogen activator receptor has been reported to activate the FPR2/ALX receptor [ 2370 ]. Furthermore, FPR2/ALX has been suggested to act as a receptor mediating the proinflammatory actions of the acute-phase reactant, serum amyloid A [ 2654 , 2717 ]. FPR2/ALX has also been reported to be activated by resolvin D1 [ 2051 ] and resolvin D3 [ 2097 ]. The agonist activity of the lipid mediators described has been questioned [ 1044 , 2255 ], which may derive from batch-to-batch differences, partial agonism or biased agonism. Results from Cooray et al. (2013) [ 535 ] have addressed this issue and the role of homodimers and heterodimers in intracellular signaling. ATL-induced conformational changes of recombinant human ALX was demonstrated using FRET analysis [ 880 ]; ATL gives a bell-shaped concentration-response relationship, inducing maximal conformational changes of ALX at 0.1–1 nM. In addition, the crystal structure of ALX was reported at 2.8 Å resolution [ 449 ]. A receptor selective for LXB 4 has been suggested from functional studies [ 80 , 1771 , 2413 ]. Note that the data for FPR2/ALX are also reproduced on the Formylpeptide receptor pages . Oxoeicosanoid receptors (OXER1, nomenclature agreed by the NC-IUPHAR subcommittee on Leukotriene receptors [ 305 ]) are activated by endogenous chemotactic eicosanoid ligands oxidised at the C-5 position, with 5-oxo-ETE the most potent agonist identified for this receptor. Initial characterization of the heterologously expressed OXER1 suggested that polyunsaturated fatty acids, such as docosahexaenoic acid and EPA , acted as receptor antagonists [ 1168 ].

G protein-coupled receptors → Neurotensin receptors Neurotensin receptors ( nomenclature as recommended by NC-IUPHAR [ 789 ]) are activated by the endogenous tridecapeptide neurotensin (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) derived from a precursor ( NTS , 30990 ), which also generates neuromedin N, an agonist at the NTS 2 receptor. [ 3 H]neurotensin (human, mouse, rat) and [ 125 I]neurotensin (human, mouse, rat) may be used to label NTS 1 and NTS 2 receptors at 0.1–0.3 and 3–5 nM concentrations respectively. Neurotensin ( NTS , P30990 ) appears to be a low-efficacy agonist at the NTS 2 receptor [ 2949 ], while the NTS 1 receptor antagonist meclinertant is an agonist at NTS 2 receptors [ 2949 ]. An additional protein, provisionally termed NTS 3 (also known as NTR3, gp95 and sortilin; ENSG00000134243 ), has been suggested to bind lipoprotein lipase and mediate its degradation [ 2073 ]. It has been reported to interact with the NTS 1 receptor [ 1826 ] and the NTS 2 receptor [ 198 ], and has been implicated in hormone trafficking and/or neurotensin uptake. A splice variant of the NTS 2 receptor bearing 5 transmembrane domains has been identified in mouse [ 275 ] and later in rat [ 2219 ]. The neurotensinergic system is implicated in various physiological and pathological processes related to neuropsychiatric and metabolic functions, cancer growth, food, and drug intake [ 1247 ].

G protein-coupled receptors → Parathyroid hormone receptors The parathyroid hormone receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Parathyroid Hormone Receptors [ 857 ]) are class B G protein-coupled receptors. The parathyroid hormone (PTH)/parathyroid hormone-related protein (PTHrP) receptor (PTH1 receptor) is activated by: PTH ( PTH , P01270 ) (84 amino acids), and PTHrP ( PTHLH , P12272 ) (141 amino-acids) and related N-terminal peptides (PTH-(1–34), PTHrP-(1–36) ( PTHLH , P12272 )). The parathyroid hormone 2 receptor (PTH2 receptor) is activated by the precursor-derived peptide TIP39 ( PTH2 , Q96A98 ) (39 amino acids) and PTH. [ 125 I]PTH may be used to label both PTH1 and PTH2 receptors. The structure of a long-active PTH analogue (LA-PTH, an hybrid of PTH-(1–13) and PTHrP-(14–36)) bound to the PTH1 receptor-G s complex has been resolved by cryo-electron microscopy [ 3247 ]. Another structure of a PTH-(1–34) analog bound to a thermostabilized inactive PTH1 receptor has been obtained with X-ray crytallography [ 708 ]. The parathyroid hormone type 1 receptor (PTH1R) is the canonical GPCR for PTH and PTHrP. It is coupled to G s and G q and regulates the development of bone, heart, mammary glands and other tissues in response to PTHrP, and blood concentrations of calcium and phosphate ions, as well as vitamin D, in response to PTH. Another important action of the PTH/PTHR system is to stimulate bone formation when the hormone is intermittently administrated (daily injection). Although PTH ( PTH , P01270 ) is an agonist at human PTH2 receptors, it fails to activate the rodent orthologues. TIP39 ( PTH2 , Q96A98 ) is a weak antagonist at PTH1 receptors [ 1309 ].

A number of pseudogenes have been identified in the human genome, which, in some cases, have a shared ancestry with functional G protein-coupled receptors in other species, including rats and mice. A curated list includes: ADGRE4P , GNRHR2 , GPR79 , HTR5BP , NPY6R , TAAR3P , TAAR4P , TAAR7P , TAS2R12P , TAS2R15P , TAS2R18P , TAS2R2P , TAS2R62P , TAS2R63P , TAS2R64P , TAS2R67P , TAS2R68P , TAS2R6P . A more detailed listing containg further information can be viewed here .

G protein-coupled receptors → Vasopressin and oxytocin receptors Vasopressin (AVP) and oxytocin (OT) receptors ( nomenclature as recommended by NC-IUPHAR [ 789 ]) are activated by the endogenous cyclic nonapeptides vasopressin ( AVP , P01185 ) and oxytocin ( OXT , P01178 ). These peptides are derived from precursors which also produce neurophysins (neurophysin I for oxytocin; neurophysin II for vasopressin). Vasopressin and oxytocin differ at only 2 amino acids (positions 3 and 8). There are metabolites of these neuropeptides that may be biologically active [ 609 ]. Vasopressin and OT receptors have a characteristic and sometimes overlapping distribution in a number of tissues including brain. There are phylogenetic, ontogenetic and sex-specific differences in the levels and distribution of these receptors, particularly in the brain. The receptors display significant species-specific differences, with many ligands demonstrating varying affinity and/or efficacy at human receptors in comparison to those of other species [ 349 , 474 ]. For example desmopressin (dDAVP) is more V 2 selective in the rat than in the human [ 2457 ], agonist d[Cha 4 ]AVP is selective only for the human and bovine V 1B receptors [ 627 ], while d[Leu 4 Lys 8 ]VP has high affinity for the rat V 1B receptor [ 2202 ], and agonist [Thr 4 ,Gly 7 ]OT is selective at mouse, rat and human OT receptors [ 349 ]. Terlipressin is a V 1A , V 1B and V 2 receptor agonist with relevant clinical applications [ 523 , 1711 ]. The gene encoding the V 2 receptor is polymorphic in man, underlying Arginine Vasopressin Deficiency (AVP-D; formerly nephrogenic diabetes insipidus) [ 221 , 490 , 1640 ]. Knockouts of vasopressin and OT receptors have system-specific defects ( e.g ., impaired ability to concentrate urine in V 2 receptor knockouts) which include behavioural deficits (principally in V 1A , V 1B and OT receptor knockouts) [ 2390 ]. [ 3 H]d(CH 2 ) 5 [Tyr(Me) 2 ]AVP (V 1A antagonist), [ 3 H]desGly-NH 2 [D-Ile 2 ,Ile 4 ]VP and [ 3 H]dDAVP (V 2 agonists) radiolabelled compounds formerly used to pharmacologically characterize vasopressin and OT receptors are no longer available.

G protein-coupled receptors → Glycoprotein hormone receptors Glycoprotein hormone receptors ( provisional nomenclature [ 789 ]) are activated by a non-covalent heterodimeric glycoprotein made up of a common α chain ( glycoprotein hormone common alpha subunit ( CGA , P01215 ) CGA , P01215 ), with a unique β chain that confers the biological specificity to FSH ( CGAFSHB , P01215 P01225 ), LH ( CGALHB , P01215 P01229 ), hCG ( CGACGB3 , P01215 P01233 ) or TSH ( CGATSHB , P01215 P01222 ). There is binding cross-reactivity across the endogenous agonists for each of the glycoprotein hormone receptors. The deglycosylated hormones appear to exhibit reduced efficacy at these receptors [ 591 , 2456 ].

G protein-coupled receptors (GPCRs) are the largest class of membrane proteins in the human genome. The term “7TM receptor” is commonly used interchangeably with “GPCR”, although there are some receptors with seven transmembrane domains that do not signal through G proteins. GPCRs share a common architecture, each consisting of a single polypeptide with an extracellular N-terminus, an intracellular C-terminus and seven hydrophobic transmembrane domains (TM1-TM7) linked by three extracellular loops (ECL1-ECL3) and three intracellular loops (ICL1-ICL3). About 800 GPCRs have been identified in man, of which about half have sensory functions, mediating olfaction (~400), taste (33), light perception (10) and pheromone signalling (5) [ 1943 ]. The remaining ~350 non-sensory GPCRs mediate signalling by ligands that range in size from small molecules to peptides to large proteins; they are the targets for the majority of drugs in clinical usage [ 2148 , 2346 ], although only a minority of these receptors are exploited therapeutically. The first classification scheme to be proposed for GPCRs [ 1464 ] divided them, on the basic of sequence homology, into six classes. These classes and their prototype members were as follows: Class A (rhodopsin-like), Class B (secretin receptor family), Class C (metabotropic glutamate), Class D (fungal mating pheromone receptors), Class E (cyclic AMP receptors) and Class F (frizzled/smoothened). Of these, classes D and E are not found in vertebrates. An alternative classification scheme “GRAFS” [ 2510 ] divides vertebrate GPCRs into five classes, overlapping with the A-F nomenclature, viz : Glutamate family ( class C ), which includes metabotropic glutamate receptors, a calcium-sensing receptor and GABA B receptors, as well as three taste type 1 receptors and a family of pheromone receptors (V2 receptors) that are abundant in rodents but absent in man [ 1943 ]. Rhodopsin family ( class A ), which includes receptors for a wide variety of small molecules, neurotransmitters, peptides and hormones, together with olfactory receptors, visual pigments, taste type 2 receptors and five pheromone receptors (V1 receptors). Adhesion family GPCRs are phylogenetically related to class B receptors, from which they differ by possessing large extracellular N-termini that are autoproteolytically cleaved from their 7TM domains at a conserved “GPCR proteolysis site” (GPS) which lies within a much larger (~320 residue) “GPCR autoproteolysis-inducing” (GAIN) domain, which in terms of evolution is an ancient motif also found in polycystic kidney disease 1 (PKD1)-like proteins, which has been suggested to be both required and sufficient for autoproteolysis [ 2288 ]. Frizzled family consists of 10 Frizzled proteins (FZD 1–10 ) and Smoothened (SMO). The FZDs are activated by secreted lipoglycoproteins of the WNT family, whereas SMO is indirectly activated by the Hedgehog (HH) family of proteins acting on the transmembrane protein Patched (PTCH). Secretin family, encoded by 15 genes in humans. The ligands for receptors in this family are polypeptide hormones of 27–141 amino acid residues; nine of the mammalian receptors respond to ligands that are structurally related to one another (glucagon, glucagon-like peptides (GLP-1, GLP-2), glucose-dependent insulinotropic polypeptide (GIP), secretin, vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP) and growth-hormone-releasing hormone (GHRH)) [ 1053 ].

G protein-coupled receptors → Melanocortin receptors Melanocortin receptors ( provisional nomenclature as recommended by NC-IUPHAR [ 789 ]) are activated by members of the melanocortin family ( α-MSH ( POMC , P01189 ), β-MSH ( POMC , P01189 ) and γ-MSH ( POMC , P01189 ) forms; δ form is not found in mammals) and adrenocorticotrophin ( ACTH ( POMC , P01189 )). Endogenous antagonists include agouti ( ASIP , P42127 ) and agouti-related protein ( AGRP , O00253 ). ACTH(1–24) was approved by the US FDA as a diagnostic agent for adrenal function test. Setmelanotide was approved by the US FDA for weight management in patients with POMC, PCSK1 or LEPR defiency, bremelanotide was approved by the US FDA for generalized hypoactive sexual desire disorder in premenopausal women, and NDP-MSH ( afamelanotide ) was approved by the EMA for the treatment of erythropoietic protoporphyria. Several synthetic melanocortin receptor agonists are under clinical development. Polymorphisms of the MC 1 receptor have been linked to variations in skin pigmentation. Defects of the MC 2 receptor underlie familial glucocorticoid deficiency. Polymorphisms of the MC 4 receptor have been linked to obesity [ 412 , 751 ].

G protein-coupled receptors → Metabotropic glutamate receptors Metabotropic glutamate (mGlu) receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Metabotropic Glutamate Receptors [ 2521 ]) are a family of G protein-coupled receptors activated by the neurotransmitter glutamate [ 971 ]. The mGlu family is composed of eight members (named mGlu1 to mGlu 8 ) which are divided in three groups based on similarities of agonist pharmacology, primary sequence and G protein coupling to effector: Group-I (mGlu 1 and mGlu 5 ), Group-II (mGlu 2 and mGlu 3 ) and Group-III (mGlu 4 , mGlu 6 , mGlu 7 and mGlu 8 ) (see Further reading). Structurally, mGlu are composed of three juxtaposed domains: a core G protein-activating seven-transmembrane domain (TM), common to all GPCRs, is linked via a rigid cysteine-rich domain (CRD) to the Venus Flytrap domain (VFTD), a large bi-lobed extracellular domain where glutamate binds. mGlu form constitutive dimers, cross-linked by a disulfide bridge. The structures of the VFTD of mGlu 1 , mGlu 2 , mGlu 3 , mGlu 5 and mGlu 7 have been solved [ 1525 , 1948 , 2008 , 2870 ]. The structure of the 7 transmembrane (TM) domains of both mGlu1 and mGlu5 have been solved, and confirm a general helical organisation similar to other GPCRs, although the helices appear more compacted [ 495 , 671 , 3105 ]. Recent advances in cryo-electron microscopy have provided structures of full-length mGlu receptor homodimers [ 1454 , 1687 ], heterodimers [ 681 , 1192 ], and new insights into activation mechanisms [ 374 , 375 , 1499 ]. Studies have revealed the possible formation of heterodimers between either group-I receptors, or within and between group-II and -III receptors [ 675 ]. First characterised in transfected cells, co-localisation and specific pharmacological properties suggest the existence of such heterodimers in the brain [ 1009 , 1689 , 1876 , 1961 , 2086 , 3189 ]. Beyond heteromerisation with other mGlu receptor subtypes, increasing evidence suggests mGlu receptors form heteromers and larger order complexes with class A GPCRs (reviewed in [ 971 ]). The endogenous ligands of mGlu are L-glutamic acid , L-serine-O-phosphate , N-acetylaspartylglutamate ( NAAG ) and L-cysteine sulphinic acid . Group-I mGlu receptors may be activated by 3,5-DHPG and ( S )-3HPG [ 287 ] and antagonised by (S)-hexylhomoibotenic acid [ 1774 ]. Group-II mGlu receptors may be activated by LY389795 [ 1949 ], LY379268 [ 1949 ], eglumegad (also refered to as LY354470 ) [ 2523 , 3111 ], DCG-IV and (2 R ,3 R )-APDC [ 2524 ], and antagonised by eGlu [ 1267 ] and LY307452 [ 735 , 3050 ]. Group-III mGlu receptors may be activated by L-AP4 and ( R,S )-4-PPG [ 865 ]. An example of an antagonist selective for mGlu receptors is LY341495 , which blocks mGlu 2 and mGlu 3 at low nanomolar concentrations, mGlu 8 at high nanomolar concentrations, and mGlu 4 , mGlu 5 , and mGlu 7 in the micromolar range [ 1422 ]. In addition to orthosteric ligands that directly interact with the glutamate recognition site, allosteric modulators that recognise distinct sites primarily within the TM domain have been described. Negative allosteric modulators are listed separately. Positive allosteric modulators potentiate orthosteric agonist responses solely, or may also possess intrinsic agonist activity. The activity of NAAG as an agonist at mGlu 3 receptors was questioned on the basis of contamination with glutamate [ 484 , 817 ], but this has been refuted [ 2040 ]. Many pharmacological agents have not been fully tested across all known subtypes of mGlu receptors and may have unappreciated biased or neutral activity at other subtypes [ 1102 ]. Potential differences linked to the species ( e.g. human versus rat or mouse) of the receptors and the receptor splice variants are generally not known. The influence of receptor expression level on pharmacology and selectivity has not been controlled for in most studies, particularly those involving functional assays of receptor coupling. DCG-IV also exhibits agonist activity at NMDA glutamate receptors [ 2900 ], and is an antagonist at all Group-III mGluRs with an IC 50 of 30μM. A potential novel metabotropic glutamate receptor coupled to phosphoinositide turnover has been observed in rat brain; it is activated by 4-methylhomoibotenic acid (ineffective as an agonist at recombinant Group I metabotropic glutamate receptors), but is resistant to LY341495 [ 503 ]. There are also reports of a distinct metabotropic glutamate receptor coupled to phospholipase D in rat brain, which does not readily fit into the current classification [ 1442 , 2198 ] A related class C receptor composed of two distinct subunits, T1R1 + T1R3 is also activated by glutamate and is responsible for umami taste detection.

G protein-coupled receptors → Neuropeptide Y receptors Neuropeptide Y (NPY) receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Neuropeptide Y Receptors [ 1893 ]) are activated by the endogenous peptides neuropeptide Y ( NPY , P01303 ), neuropeptide Y-(3–36), peptide YY ( PYY , P10082 ), PYY-(3–36) and pancreatic polypeptide ( PPY , P01298 ) (PP). The receptor originally identified as the Y3 receptor has been identified as the CXCR4 chemokine recepter (originally named LESTR, [ 1724 ]). The y6 receptor is a functional gene product in mouse, absent in rat, but contains a frame-shift mutation in primates producing a truncated non-functional gene [ 969 ]. Three-dimensional structures have been determined for subtype active receptors Y 1 , Y 2 and Y 4 [ 1341 , 2789 ] and inactive antagonist bound Y 1 and Y 2 receptors [ 2788 , 3170 ]. Many of the agonists exhibit differing degrees of selectivity dependent on the species examined. For example, the potency of PP is greater at the rat Y 4 receptor than at the human receptor [ 729 ]. In addition, many agonists lack selectivity for individual subtypes, but can exhibit comparable potency against pairs of NPY receptor subtypes, or have not been examined for activity at all subtypes. [ 125 I]-PYY or [ 125 I]-NPY can be used to label Y 1 , Y 2 , Y 5 and y 6 subtypes non-selectively, while [ 125 I][cPP(1–7) , NPY(19–23) , Ala 31 , Aib 32 , Gln 34 ]hPP may be used to label Y 5 receptors preferentially (note that cPP denotes chicken peptide sequence and hPP is the human sequence). The Y 1 agonists indicated are selective relative to Y 2 receptors. BIBP3226 is selective relative to Y 2 , Y 4 and Y 5 receptors [ 896 ]. NPY-(13–36) is Y 2 selective relative to Y 1 and Y 5 receptors. PYY-(3–36) is Y 2 selective relative to Y 1 receptors, and new long-acting analogues of PYY(3–36) exhibit improved Y 2 selectivity. Note that Pro34-containing NPY and PYY can also bind Y 4 and Y 5 , thus they are selective only relative to Y 2 . The y 6 receptor is a pseudogene in humans, but is functional in mouse, rabbit and some other mammals. Human Y 4 has several naturally occurring sequence variants [ 2579 ] and the human NPY4R gene displays extensive gene copy number variation [ 2578 ].

G protein-coupled receptors → Oxoglutarate receptor Nomenclature as recommended by NC-IUPHAR [ 586 ].

G protein-coupled receptors → Prokineticin receptors Prokineticin receptors, PKR 1 and PKR 2 ( provisional nomenclature as recommended by NC-IUPHAR [ 789 ]) respond to the cysteine-rich 81–86 amino-acid peptides prokineticin-1 ( PROK1 , Q9HC23 ) (also known as endocrine gland-derived vascular endothelial growth factor, mambakine) and prokineticin-2 ( PROK2 , Q9HC23 ) (protein Bv8 homologue). An orthologue of PROK1 from black mamba ( Dendroaspis polylepi s) venom, mamba intestinal toxin 1 ( MIT1 , [ 2535 ]) is a potent, non-selective agonist at prokineticin receptors [ 1832 ], while Bv8 , an orthologue of PROK2 from amphibians ( Bombina sp. , [ 1938 ]), is equipotent at recombinant PKR 1 and PKR 2 [ 2046 ], and has high potency in macrophage chemotaxis assays, which are lost in PKR 1 -null mice. Genetic mutations in PROKR1 are associated with Hirschsprung’s disease [ 2438 ], while genetic mutations in PROKR2 are associated with hypogonadotropic hypogonadism with anosmia [ 658 ], hypopituitarism with pituitary stalk interruption [ 2375 ] and Hirschsprung’s disease [ 2438 ]. PKR 2 has been recently identified as a receptor for T. cruzi natural infection [ 1391 ]. PROK2 neuropeptide signalling via PKR 2 on spinal neurons generates pleasant touch sensation [ 1701 ].

G protein-coupled receptors → Somatostatin receptors Somatostatin (somatotropin release inhibiting factor) is an abundant neuropeptide, which acts on five subtypes of somatostatin receptor (SST 1 -SST 5 ; nomenclature as agreed by the NC-IUPHAR Subcommittee on Somatostatin Receptors [ 1001 ]). Activation of these receptors produces a wide range of physiological effects throughout the body including the inhibition of secretion of many hormones. Endogenous ligands for these receptors are somatostatin-14 ( SRIF-14 ( SST , P61278 )) and somatostatin-28 ( SRIF-28 ( SST , P61278 )). Cortistatin-14 {Mouse, Rat} has also been suggested to be an endogenous ligand for somatostatin receptors [ 602 ]. [ 125 I]Tyr 11 -SRIF-14 , [ 125 I]LTT-SRIF-28 , [ 125 I]CGP 23996 and [ 125 I]Tyr 10 -CST14 may be used to label somatostatin receptors nonselectively. A number of nonpeptide subtype-selective agonists have been synthesised [ 2409 ]. Octreotide and lanreotide are being used in the treatment of SST 2 -expressing neuroendocrine tumors and pasireotide for SST 5 -expressing neuroendocrine tumors. A novel peptide somatostatin analogue, veldoreotide (COR-005), has affinity for SST 2 , SST 4 and SST 5 receptors and is a potent inhibitor of GH secretion [ 2256 , 2594 ].

G protein-coupled receptors → Acetylcholine receptors (muscarinic) Muscarinic acetylcholine receptors (mAChRs) ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Muscarinic Acetylcholine Receptors [ 398 ]) are activated by the endogenous agonist acetylcholine [ 460 , 1263 , 1384 ]. All five (M1-M5) mAChRs are ubiquitously expressed in the human body and are therefore attractive targets for many disorders. Functionally, M 1 , M 3 , and M 5 mAChRs preferentially couple to G q/11 proteins, whilst M 2 and M 4 mAChRs predominantly couple to G i/o proteins. Both agonists and antagonists of mAChRs are clinically approved drugs, including pilocarpine for the treatment of elevated intra-ocular pressure and glaucoma, and atropine for the treatment of bradycardia and poisoning by muscarinic agents such as organophosphates. Of note, it has been observed that mAChRs dimerise reversibly [ 1108 ] and that dimerisation/oligomerisation can be affected by ligands [ 1661 , 1821 ]. Atomic structures for all five mAChRs bound to antagonists have been determined [ 1012 , 2736 , 2807 , 2962 , 3173 ]. Structures of agonist-bound M 1 , M 2 , M 3 , and M 4 mAChRs [ 345 , 1505 , 2995 , 3130 , 3232 ] and β 2 -arrestin-bound M 2 mAChR have been reported [ 2688 ]. These structures show that the orthosteric binding site of this family of receptor is absolutely conserved and, as a consequence, explain why highly selective orthosteric ligand binding to any specific mAChR has been notoriously difficult to achieve. As such, it is common to assess the rank order of affinity for a range of antagonists with limited selectivity ( e.g. , 4-DAMP , darifenacin , pirenzepine , AFDX384 ) to identify the involvement of particular subtypes-although caution should be used in the design and interpretation of such experiments due to the lack of absolute ligand subtype selectivity [ 2009 ]. Some ligands may display selectivity at the level of function ( e.g ., xanomeline ) or binding kinetics ( e.g. , tiotropium ) [ 2276 , 2571 , 2799 ]. In addition, structures of the M 3 and M 4 mAChR DREADDS (designer receptors exclusively activated by designer drugs) have been reported providing insights into orthosteric ligand selectivity for these chemogenetic tools [ 3232 ]. Structures of the M 2 and M 4 mAChRs in complex with allosteric modulators [ 1505 , 1779 , 2963 , 2995 ] have validated numerous pharmacological studies that indicated the presence of a common mAChR allosteric site located at the extracellular entrance to these receptors. In addition, a structure of the M 1 mAChR with muscarinic toxin 7 (MT7) bound to the common allosteric site has provided insight into the extreme subtype selectivity of MT7 [ 1779 ]. Allosteric ligands proposed to bind to this common allosteric site include gallamine , strychnine , C 7 /3-phth , brucine . Additionally, a second allosteric site has been proposed on the mAChRs based on pharmacological analyses of the actions of compounds such as KT 5720 , WIN 62,577 , WIN 51,708 , staurosporine and amiodarone [ 344 , 1575 , 1576 , 2684 ]. In the presence of the orthosteric ligand, allosteric modulators can exert positive, negative, or neutral cooperativity with that ligand. Direct receptor activation via an allosteric site has been reported for a number of allosteric ligands of the mAChRs [ 595 , 1587 , 1590 , 1760 , 2037 , 2038 ]. ‘Atypical agonists’ are ligands that have been suggested to have bitopic binding modes for at least one subtype whereby the agonist occupies both the orthosteric and allosteric sites [ 109 , 1383 , 2904 ]. Several mAChR subtype selective PET radioligands have been reported, with [ 11 C]MK-6884 showing specific activity in patients with Alzheimer’s disease [ 568 , 1653 ].

G protein-coupled receptors → Adrenoceptors The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [ 355 , 1123 ]. The three α 1 -adrenoceptor subtypes α 1A , α 1B and α 1D are activated by the endogenous agonists (−)-adrenaline and (−)-noradrenaline . - (−)phenylephrine , methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for α 1 -relative to α 2 -adrenoceptors. [ 3 H]prazosin and HEAT (BE2254) (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca 2+ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin-QAPB) are used to examine cellular localisation of α 1 -adrenoceptors. α 1 -Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia ( alfuzosin , doxazosin , terazosin , tamsulosin and silodosin , with the last two compounds being α1 A -adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension ( doxazosin , terazosin ). The α 1 - and β 2 -adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of α 1 -adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are α 1 -adrenoceptor antagonists contributing to side effects such as orthostatic hypotension. The three α1-adrenoceptor subtypes are α 1A , α 1B and α 1D . The previously described α 1C -adrenoceptor is a species homologue that corresponds to the pharmacologically defined α 1A -adrenoceptor [ 1123 ]. Some tissues possess α 1A -adrenoceptors (termed α 1L -adrenoceptors [ 792 , 1973 ]) that display relatively low affinity in functional and binding assays for prazosin indicative of different receptor states or locations. α 1A -Adrenoceptor C-terminal splice variants form homo- and heterodimers, and do not generate a functional α 1L -adrenoceptor [ 2340 ]. Recombinant α 1D -adrenoceptors have been shown in some heterologous systems to be mainly located intracellularly but cell-surface localization is encouraged by truncation of the N-terminus, or by co-expression and formation of heterodimers of with α 1B -α 1B - or β 2 –β 2 -adrenoceptors [ 1014 , 2879 ]. In blood vessels all three α 1- -adrenoceptor subtypes are located both at the cell surface and intracellularly [ 1878 , 1879 ]. Signalling is predominantly via G q/11 but α 1 -adrenoceptors also couple to G i/o , G s and G 12/13 . Several α 1A -adrenoceptor agonists display ligand directed signalling bias relative to noradrenaline [ 739 ] although some bias appears to relate to off-target activity [ 569 ]. There are also differences between subtypes in coupling efficiency to different pathways. In vascular smooth muscle, the potency of agonists is related to the predominant subtype, α 1D -conveying greater agonist sensitivity compared to α 1A -adrenoceptors [ 785 ]. The three α 2 -adrenoceptor subtypes α 2A , α 2B and α 2C are activated by (−)-adrenaline and with lower potency by (−)-noradrenaline . Brimonidine (UK14304) and talipexole are agonists and rauwolscine and yohimbine antagonists selective for α 2 -relative to α 1 -adrenoceptors. [ 3 H]rauwolscine , [ 3 H]brimonidine (UK14304) and [ 3 H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the α 2A -adrenoceptor. Multiple mutations of α 2 -adrenoceptors have been described, some associated with alterations in function. Presynaptic α 2 -adrenoceptors regulate many functions in the nervous system. The α 2 -adrenoceptor agonists clonidine , guanabenz and brimonidine (UK14304) affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. Clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. Dexmedetomidine (also xylazine ) is increasingly used as a sedative and analgesic in human [ 145 ] and veterinary medicine and has sympatholytic and anxiolytic properties. The α 2 -adrenoceptor antagonist mirtazapine is used as an anti-depressant. The α 2B subtype appears to be involved in neurotransmission in the spinal cord and α 2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools. The three α 2 -adrenoceptor subtypes are termed α 2A , α 2B and α 2C . ARC-239 and prazosin show some selectivity for α 2B - and α 2C -adrenoceptors over α 2A -adrenoceptors. Oxymetazoline is an imidazoline partial agonist that also binds to non-GPCR binding sites for imidazolines, classified as I 1 , I 2 and I 3 [ 576 ] at which catecholamines have a low affinity, while rilmenidine and moxonidine are selective ligands with hypotensive effects in vivo . I 1 -imidazoline recognition sites cause central inhibition of sympathetic tone, I 2 -imidazoline sites are an allosteric binding site on monoamine oxidase B, and I 3 -imidazoline sites regulate insulin secretion from pancreatic β-cells. α 2A -adrenoceptor stimulation reduces insulin secretion from β-islets [ 3162 ], with a polymorphism in the 5’-UTR of the ADRA2A gene being associated with increased receptor expression in β-islets and heightened susceptibility to diabetes [ 2419 ]. The α 2A - and α 2C -adrenoceptors form homodimers [ 2638 ]. Heterodimers between α 2A - and either the α 2c -adrenoceptor or μ opioid peptide receptor exhibit altered signalling and trafficking properties compared to the individual receptors [ 2638 , 2782 , 2943 ]. Signalling by α 2 -adrenoceptors is primarily via G i/o , although the α 2A -adrenoceptor also couples to G s [ 700 ]. Imidazoline compounds display bias relative to each other at the α 2A -adrenoceptor [ 2189 ]. The noradrenaline reuptake inhibitor desipramine acts directly on α 2A -adrenoceptors to promote internalisation via recruitment of β-arrestin [ 543 ]. The structure of the α 2B -adrenoceptor has recently been determined by cryo-EM in complex with dexmedetomidine and Gα o at a resolution of 2.9 Å providing insights into the structural requirements required for interactions with α 2 -adrenoceptor agonists [ 3204 ]. The three β-adrenoceptor subtypes β 1 , β 2 and β 3 are activated by the endogenous agonists (−)-adrenaline and (−)-noradrenaline . Isoprenaline is selective for β-adrenoceptors relative to α 1 - and α 2 -adrenoceptors, while propranolol (p K i 8.2–9.2) and cyanopindolol (p K i 10.0–11.0) are relatively selective antagonists for β 1 - and β 2 -relative to β 3 -adrenoceptors. (−)-noradrenaline , xamoterol and (−)-Ro 363 show selectivity for β 1 -relative to β 2 -adrenoceptors. Pharmacological differences exist between human and mouse β 3 -adrenoceptors, and the ‘rodent selective’ agonists BRL 37344 and CL316243 have low efficacy at the human β 3 -adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human β 3 -adrenoceptors [ 88 ]. β 3 -Adrenoceptors are resistant to blockade by propranolol , but can be blocked by high concentrations of bupranolol . SR59230A has reasonably high affinity at β 3 -adrenoceptors, but does not discriminate between the three β-subtypes [ 1895 ] whereas L-748337 is more selective. [ 125 I]- cyanopindolol , [ 125 I]-hydroxy benzylpindolol and [ 3 H]- alprenolol are high affinity radioligands that label β 1 - and β 2 -adrenoceptors and β 3 -adrenoceptors can be labelled with higher concentrations (nM) of [ 125 I]- cyanopindolol together with β 1 - and β 2 -adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR- CGP12177 can be used to track β-adrenoceptors at the cellular level [ 8 ]. Somewhat selective β 1 -adrenoceptor agonists ( denopamine , dobutamine ) are used short term to treat cardiogenic shock but, chronically, reduce survival. β 1 -Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias ( atenolol , bisoprolol , esmolol ) and cardiac failure ( metoprolol , nebivolol ) but also in combination with other treatments to treat hypertension ( atenolol , betaxolol , bisoprolol , metoprolol and nebivolol ) [ 3087 ]. Cardiac failure is also treated with carvedilol that blocks β 1 - and β 2 -adrenoceptors, as well as α 1 -adrenoceptors. Short ( salbutamol , terbutaline ) and long ( formoterol , salmeterol ) acting β 2 -adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation β-adrenoceptor antagonists ( propranolol ) block both β 1 - and β 2 -adrenoceptors and there are no β 2 -adrenoceptor-selective antagonists used therapeutically. The β 3 -adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that β-adrenoceptor antagonists can reduce metastasis in certain types of cancer [ 1127 ]. The three β-adrenoceptors are termed β 1 , β 2 and β 3 . [ 125 I]ICYP can be used to define either β 1 - or β 2 -adrenoceptors when conducted in the presence of a β 1 - or a β 2 -adrenoceptor-selective antagonist. A fluorescent analogue of CGP 12177 is used to study β-adrenoceptors in living cells [ 132 ]. [ 125 I]ICYP at higher (nM) concentrations has been used to label β 3 -adrenoceptors in systems with few if any other β-adrenoceptor subtypes. The β 3 -adrenoceptor has an intron in the coding region, but splice variants have only been described for the mouse [ 740 ], where the isoforms display different signalling characteristics [ 1206 ]. There are three β-adrenoceptors in turkey (termed the tβ, tβ3c and tβ4c) with pharmacology that differs from the human β-adrenoceptors [ 127 ]. Numerous polymorphisms have been described for the β-adrenoceptors; some are associated with altered signalling and trafficking, susceptibility to disease and/or altered responses to pharmacotherapy [ 1672 ]. All β-adrenoceptors couple to G s (activating adenylyl cyclase and elevating cAMP levels), but the β 2 - and β 3 -adrenoceptors in particular can also activate G i and the β 2 -adrenoceptor activates β-arrestin-mediated signalling. Many β 1 - and β 2 -adrenoceptor antagonists are agonists at β 3 -adrenoceptors ( CL316243 , CGP 12177 and carazolol ). Many ‘antagonists’ of cAMP accumulation, for example carvedilol and bucindolol, weakly activate MAP kinase pathways [ 130 , 741 , 835 , 836 , 2485 , 2486 ] and thus display biased agonism. Bupranolol acts as a neutral antagonist in most systems so far examined. Agonists also display biased signalling at the β 2 -adrenoceptor via G s or arrestins [ 677 ]. X-ray crystal structures have been described of the agonist bound [ 3020 ] and antagonist bound forms of the β 1 - [ 3021 ], agonist-bound [ 464 ] and antagonist-bound forms of the β 2 -adrenoceptor [ 2347 , 2418 ], as well as a fully active agonist-bound, G s protein-coupled β 2 -adrenoceptor [ 2348 ], as well as providing insights into the structural requirements for agonist, partial agonist, antagonist, G protein and β-arrestin coupling [ 3038 ]. Structures have also been described for negative allosteric modulators of the β 2 -adrenoceptor [ 1719 ]. Cryo-EM studies have also been recently described that provide a structural framework for agonist mediated signal transduction [ 2716 ]. The agonists carvedilol and bucindolol bind to a site on the β 1 -adrenoceptor involving contacts in TM2, 3, and 7 and extracellular loop 2 that may facilitate coupling to arrestins [ 3021 ]. Compounds displaying β-arrestin-biased signalling at the β 2 -adrenoceptor have a greater effect on the conformation of TM7, whereas full agonists for G s coupling promote movement of TM5 and TM6 [ 1713 ]. Recent studies using NMR spectroscopy demonstrate significant conformational flexibility in the β 2 -adrenoceptor that is stabilized by both agonist and G proteins highlighting the dynamic nature of interactions with both ligand and downstream signalling partners [ 1410 , 1802 , 2099 ]. Such flexibility likely has consequences for our understanding of allosterism and biased agonism, and for the future therapeutic exploitation of these phenomena.

G protein-coupled receptors → Formylpeptide receptors The human formylpeptide receptor subfamily of GPCRs (FPR: nomenclature described in [ 2311 , 3179 ] [ 1 , 2 ]) comprises three members (FPR1, FPR2, and FPR3). Two of these, FPR1 and FPR2, recognize peptides bearing N-terminal formyl-Met from invading bacteria [ 1498 ] or mitochondria. These peptides function as danger signals in innate immunity. FPR1 and FPR2 are promiscuous and also recognize several non-formylated peptides, proteins, lipids and small molecules [ 1498 , 2311 , 3179 ] of which some are able to initiate signals (balanced or biased) that mediate pro-inflammatory and/or inflammation resolving effects [ 1880 , 2218 ]. In contrast, FPR3 remains less well-characterized in part due to the absence of selective ligands which has significantly impeded progress in its functional characterization [ 632 , 2324 ]. Note that the data for FPR2 are also reproduced on the leukotriene receptor page under the heading “the FPR2/ALX receptor”. It should also be noted that some of the specialized pro-resolving mediators are, in addition to the FPRs, also recognized by other GPCRs and they are present at very low levels as endogenous mediators for resolution of inflammation [ 2504 ]. Since potency for different FPR agonists determined in many different research laboratories is dependent on the assay systems used, direct comparison of potency may be difficult for FPR agonists with anti-inflammatory and pro-resolving activities. For this reason, the pro-resolving lipid mediators are listed in one group and ligands with balanced agonistic activities are listed in another group for potency comparison. The biased signaling characteristics of some of the FPR agonists must be taken into consideration when their potencies are compared [ 880 , 1690 , 2734 ]. FPR1 has been reported to be the plague receptor on host immune cells [ 2143 ] and as co-receptor for HIV [ 3036 ], but these findings have to be further explored [ 879 ]. Some FPR2 ligands suggested to allosterically modulate receptor function activate the receptor in a classical but functionally selective mode [ 3083 ], whereas allosteric modulatory effects of other compounds cause changes in receptor conformational states and receptor signaling [ 880 ]. The 3-D structure of FPR1/2 has been solved and the FPR2 structure reveals a large binding pocket that can accommodate ligands of different shapes and sizes for the generation of different conformational changes [ 1665 ]. Studies have been conducted to explore the mechanisms by which primarily FPR2 mediates both pro-inflammatory and anti-inflammatory signaling in a ligand-dependent manner. It should be noted, however, that some of the not yet clearly identified anti-inflammatory signals, are generated by agonists that preferentially activate FPR1 [ 2310 ]. The status of FPR2 dimerization is a determining factor for ligand-specific conformational changes leading to biased signaling [ 535 ]. There is also a report on ligand concentration-dependent dual modulation of FPR2 for receptor-activation vs. anti-inflammatory activities [ 872 ], and ligand concentration-dependent modulation of FPR1 functions has also been reported [ 2997 ]. FPR ligands are attractive candidates for promoting the resolution of inflammation, enhancing innate immune defense and tuning immune responses in inflammatory/auto-immune diseases and tumor microenvironments [ 571 , 2991 ].

G protein-coupled receptors → Calcium-sensing receptor The calcium-sensing receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [ 789 ] and subsequently updated [ 1589 ]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [ 1591 ]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [ 322 , 2318 ], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [ 531 , 789 , 1138 , 2316 , 2317 ]. Indeed, L-amino acids have been identified as “co-agonists”, with both concomitant calcium and L-amino acid binding required for full receptor activation [ 886 , 3220 ]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [ 371 ] or decreased extracellular ionic strength [ 2317 ] while sensitivity is decreased by pathophysiological phosphate concentrations [ 408 ]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS. The CaS receptor has a number of physiological functions, but it is best known for its central role in parathyroid and renal regulation of extracellular calcium homeostasis [ 1038 ]. This is seen most clearly in patients with loss-of-function CaS receptor mutations who develop familial hypocalciuric hypercalcaemia (heterozygous mutations) or neonatal severe hyperparathyroidism (heterozygous, compound heterozygous or homozygous mutations) [ 1038 ] and in Casr null mice [ 426 , 1138 ], which exhibit similar increases in PTH secretion and blood calcium levels. Gain-of-function CaS mutations are associated with autosomal dominant hypocalcaemia and Bartter syndrome type V [ 1038 ]. The CaS receptor primarily couples to G q/11 , G 12/13 and G i/o [ 590 , 898 , 1188 , 2823 ], but in some cell types can couple to G s [ 1799 ]. The CaS receptor acts as a homodimer [ 849 , 3220 ], but which can only couple one G protein at a time [ 1081 , 3278 ]. However, the CaS receptor can also form heteromers with Class C GABA B [ 427 , 463 ] and mGlu1/5 receptors [ 843 ], which may introduce further complexity in its signalling capabilities. Multiple other small molecule chemotypes are positive and negative allosteric modulators of the CaS receptor [ 1392 , 2052 ]. Further, etelcalcetide is a peptide positive allosteric modulator of the receptor, that also displays weak agonist activity [ 2978 ]. Agonists and positive allosteric modulators of the CaS receptor are termed Type I and II calcimimetics, respectively, and can suppress parathyroid hormone ( PTH ( PTH , P01270 )) secretion [ 2054 ]. Computational docking using large library screens has recently identified additional potent CaS receptor positive allosteric modulators [ 1712 ]. Negative allosteric modulators are called calcilytics and can act to increase PTH ( PTH , P01270 ) secretion [ 2053 ]. Recently, nanobodies have been developed as both positive and negative allosteric modulators [ 563 , 682 ]]. Where functional pK B values are provided for allosteric modulators, this refers to ligand affinity determined in an assay that measures a functional readout of receptor activity ( i.e. a receptor signalling assay), as opposed to affinity determined in a radioligand binding assay. The functional pK B may differ depending on the signalling pathway studied. Consult the ‘ More detailed page ’ for the assay description, as well as other functional readouts.

G protein-coupled receptors → Cholecystokinin receptors Cholecystokinin receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on CCK receptors [ 2088 ]) are activated by the endogenous peptides cholecystokinin-8 ( CCK-8 ( CCK , P06307 )), CCK-33 ( CCK , P06307 ), CCK-58 ( CCK , P06307 ) and gastrin ( gastrin-17 ( GAST , P01350 )). There are only two distinct subtypes of CCK receptors, CCK 1 and CCK 2 receptors [ 1478 , 3016 ], with some alternatively spliced forms most often identified in neoplastic cells. The CCK receptor subtypes are distinguished by their peptide selectivity, with the CCK 1 receptor requiring the carboxyl-terminal heptapeptide-amide that includes a sulfated tyrosine for high affinity and potency, while the CCK 2 receptor requires only the carboxyl-terminal tetrapeptide shared by each CCK and gastrin peptides. These receptors have characteristic and distinct distributions, with both present in both the central nervous system and peripheral tissues. While a cancer-specific CCK receptor has been postulated to exist, which also might be responsive to incompletely processed forms of CCK (Gly-extended forms), this has never been isolated. An alternatively spliced form of the CCK 2 receptor in which intron 4 is retained, adding 69 amino acids to the intracellular loop 3 (ICL3) region, has been described to be present particularly in certain neoplasms where mRNA mis-splicing has been commonly observed [ 2643 ], but it is not clear that this receptor splice form plays a special role in carcinogenesis. Another alternative splicing event for the CCK 2 receptor was reported [ 2665 ], with alternative donor sites in exon 4 resulting in long (452 amino acids) and short (447 amino acids) forms of the receptor differing by five residues in ICL3, however, no clear functional differences have been observed.

G protein-coupled receptors → Lysophospholipid (S1P) receptors Sphingosine 1-phosphate (S1P) receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [ 1396 ]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene ( edg ) family [ 231 , 1927 ], the receptors are currently designated as S1P 1 R through S1P 5 R [ 231 , 1137 , 1927 ]. Their gene nomenclature has been codified as human S1PR1, S1PR2, etc . (HUGO Gene Nomenclature Committee, HGNC) and S1pr1, S1pr2, etc . for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function. All S1P receptors (S1PRs) have been knocked-out in mice constitutively and in some cases, conditionally. S1P receptors, particularly S1P 1 , are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or “chaperones”): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P 1 in multiple cell types [ 233 , 841 ]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems. Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P 1 R activation [ 1470 , 1471 ]. The structures of S1P 1 [ 1045 , 1717 , 3141 , 3202 ], S1P 2 [ 437 ], S1P 3 [ 1778 , 3245 ], and S1P 5 [ 1756 , 3205 ] are solved, and confirmed aspects of ligand binding, specificity, and receptor activation, determined previously through biochemical and genetic studies [ 232 , 1045 ]. Fingolimod (FTY720), the first FDA-approved drug to target any of the lysophospholipid receptors, binds as a phosphorylated metabolite to four of the five S1PRs, and was the first oral therapy for multiple sclerosis (MS) [ 502 ]. Second-generation S1PR modulators siponimod and ozanimod target S1P 1 and S1P 5 , while etrasimod targets S1P 1 , S1P 4 and S1P 5 ; and ponesimod targets S1P 1 alone, and all are FDA approved for the treatment of various MS forms [ 231 , 1927 ] and/or ulcerative colitis for ozanimod and etrasimod [ 2470 , 2601 ]. The mechanisms of action of fingolimod and other S1PR-modulating drugs now in development include binding S1PRs in multiple organ systems, e.g. , immune and nervous systems, although the precise nature of their receptor interactions requires clarification, although most S1P 1 effects appear to involve functional antagonism [ 522 , 982 , 983 , 2287 ]. The FDA-approved immunomodulator fingolimod (FTY720) is phosphorylated in vivo [ 39 ] to generate an agonist with activity at S1P 1 , S1P 3 , S1P 4 and S1P 5 receptors [ 306 , 1801 ]. Many of the physiological consequences of fingolimod-phosphate administration, as well as those of other currently described S1P 1 agonists, may involve functional antagonism via ubiquitination and subsequent degradation of S1P 1 [ 231 , 2139 ]. Additionally, receptor specificities of the different compounds may depend on the functional assay system utilized and from which species the receptor sequence originated.

G protein-coupled receptors → Hydroxycarboxylic acid receptors The hydroxycarboxylic acid family of receptors ( ENSFM00500000271913 , nomenclature as agreed by the NC-IUPHAR Subcommittee on Hydroxycarboxylic acid receptors [ 586 , 2108 ]) respond to organic acids, including the endogenous hydroxy carboxylic acids 3-hydroxy butyric acid and L-lactic acid , as well as the lipid lowering agents nicotinic acid (niacin), acipimox and acifran [ 2656 , 2874 , 3084 ]. These receptors were provisionally described as nicotinic acid receptors, although nicotinic acid shows submicromolar potency at HCA 2 receptors only and is unlikely to be the natural ligand [ 2874 , 3084 ]. Further closely-related GPCRs include the 5-oxoeicosanoid receptor ( OXER1 , Q8TDS5 ) and GPR31 ( O00270 ). Lactate activates HCA 1 on adipocytes in an autocrine manner. It inhibits lipolysis and thereby promotes anabolic effects. HCA 2 and HCA 3 regulate adipocyte lipolysis and immune functions under conditions of increased FFA formation through lipolysis (e.g., during fasting). HCA 2 agonists acting mainly through the receptor on immune cells exert antiatherogenic and anti-inflammatory effects. HCA 2 is also a receptor for butyrate and mediates some of the beneficial effects of short-chain fatty acids produced by gut microbiota. HCA 3 has been shown to be activated by aromatic D-amino acids, and by D-phenyllactic acid, a metabolite of gut lactic acid bacteria [ 2225 ].

G protein-coupled receptors → 5-Hydroxytryptamine receptors 5-HT receptors ( nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-HT receptors [ 1176 ] and subsequently revised [ 1058 ]) are, with the exception of the ionotropic 5-HT 3 class, GPCRs where the endogenous agonist is 5-hydroxytryptamine . The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT 2A (non-functional), 5-HT 2C (non-functional), 5-HT 4 , 5-HT 6 (non-functional) and 5-HT 7 receptors. Unique amongst the GPCRs, RNA editing produces 5-HT 2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to G q/11 and also pharmacology [ 241 , 3052 ]. Most 5-HT receptors (except 5-ht 1e and 5-ht 5b ) play specific roles mediating functional responses in different tissues (reviewed by [ 2334 , 2945 ]). Tabulated pK i and K D values refer to binding to human 5-HT receptors unless indicated otherwise. The nomenclature of 5-HT 1B /5-HT 1D receptors has been revised [ 1058 ]. Only the non-rodent form of the receptor was previously called 5-HT 1D : the human 5-HT 1B receptor (tabulated) displays a different pharmacology to the rodent forms of the receptor due to Thr335 of the human sequence being replaced by Asn in rodent receptors [ 1040 ]. Wang et al. (2013) report X-ray structures which reveal the binding modality of ergotamine and dihydroergotamine (DHE) to the 5-HT 1B receptor in comparison with the structure of the 5-HT 2B receptor [ 2984 ]; some of these drugs adopt rather different conformations depending on the target receptor [ 2207 ]. Various 5-HT receptors have multiple partners in addition to G proteins, which may affect function and pharmacology [ 1817 ]. NAS181 is a selective antagonist of the rodent 5-HT 1B receptor. Fananserin (LSD) and ketanserin bind with high affinity to dopamine D4 and histamine H 1 receptors respectively, and ketanserin is a potent α1 adrenoceptor antagonist, in addition to blocking 5-HT 2A receptors. Lysergic acid (LSD) and ergotamine show a strong preference for arrestin recruitment over G protein coupling at the 5-HT 2B receptor, with no such preference evident at 5-HT 1B receptors, and they also antagonise 5-HT 7A receptors [ 2965 ]. DHE ( dihydroergocryptine ), pergolide and cabergoline also show significant preference for arrestin recruitment over G protein coupling at 5-HT 2B receptors [ 2965 ]. The 5-HT 2B (and other 5-HT) receptors interact with immunocompetent cells [ 2153 ]. The serotonin antagonist mesulergine was key to the discovery of the 5-HT 2C receptor [ 2192 ], initially known as 5-HT 1C [ 110 ]. The human 5-HT 5A receptor may couple to several signal transduction pathways when stably expressed in C6 glioma cells [ 2089 ] and rodent prefrontal cortex (layer V pyramidal neurons) [ 939 ]. The human orthologue of the mouse 5-ht 5b receptor is non-functional (stop codons); the 5-ht 1e receptor has not been cloned from mouse, or rat, impeding definition of its function [ 1040 ]. In addition to accepted receptors, an ‘orphan’ receptor, unofficially termed 5-HT 1P , has been described [ 900 ].

G protein-coupled receptors → Platelet-activating factor receptor Platelet-activating factor (PAF, 1- O -alkyl-2-acetyl-sn-glycero-3-phosphocholine) is an ether phospholipid mediator associated with platelet coagulation, but also subserves inflammatory roles. The PAF receptor ( provisional nomenclature recommended by NC-IUPHAR [ 789 ]) is activated by PAF and other suggested endogenous ligands are oxidized phosphatidylcholine [ 1812 ] and lysophosphatidylcholine [ 2109 ]. It may also be activated by bacterial lipopolysaccharide [ 2020 ]. Note that a previously recommended radioligand ( [ 3 H]apafant ; K d 44.6 nM) is currently unavailable.

G protein-coupled receptors → Prolactin-releasing peptide receptor The precursor ( PRLH , P81277 ) for PrRP generates 31 and 20-amino-acid versions. QRFP43 (43RFa) ( QRFP , P83859 ) (named after a pyroglutamylated arginine-phenylalanine-amide peptide) is a 43 amino acid peptide derived from QRFP ( P83859 ) and is also known as P518 or 26RFa. RFRP is an RF amide-related peptide [ 1129 ] derived from a FMRFamide-related peptide precursor ( NPVF , Q9HCQ7 ), which is cleaved to generate neuropeptide SF ( NPFF , O15130 ), neuropeptide RFRP-1 ( NPVF , Q9HCQ7 ), neuropeptide RFRP-2 ( NPVF , Q9HCQ7 ) and neuropeptide RFRP-3 ( NPVF , Q9HCQ7 ) (neuropeptide NPVF). The orphan receptor GPR83 ( Q9NYM4 ) shows sequence similarities with NPFF1, NPFF2, PrRP and QRFP receptors.

G protein-coupled receptors → Proteinase-activated receptors Proteinase-activated receptors (PARs, nomenclature as agreed by the NC-IUPHAR Subcommittee on Proteinase-activated Receptors [ 1148 ]) are unique members of the GPCR superfamily activated by proteolytic cleavage of their amino terminal exodomains. Agonist proteinase-induced hydrolysis unmasks a tethered ligand (TL) at the exposed amino terminus, which acts intramolecularly at the binding site in the body of the receptor to effect transmembrane signalling. TL sequences at human PAR1–4 are SFLLRN-NH 2 , SLIGKV-NH 2 , TFRGAP-NH 2 and GYPGQV-NH 2 , respectively. With the exception of PAR3, synthetic peptides with these sequences (as carboxyl terminal amides) are able to act as agonists at their respective receptors. Several proteinases, including neutrophil elastase, cathepsin G and chymotrypsin can have inhibitory effects at PAR1 and PAR2 such that they cleave the exodomain of the receptor without inducing activation of Gαq-coupled calcium signalling, thereby preventing activation by activating proteinases but not by agonist peptides. Neutrophil elastase (NE) cleavage of PAR1 and PAR2 can however activate MAP kinase signaling by exposing a TL that is different from the one revealed by trypsin [ 2333 ]. PAR2 activation by NE regulates inflammation and pain responses [ 1993 , 3248 ] and triggers mucin secretion from airway epithelial cells [ 3255 ]. Endogenous serine proteases (EC 3.4.21.) active at the proteinase-activated receptors include: thrombin ( F2 , P00734 ), generated by the action of Factor X ( F10 , P00742 ) on liver-derived prothrombin ( F2 , P00734 ); trypsin, generated by the action of enterokinase ( TMPRSS15 , P98073 ) on pancreatic-derived trypsinogen ( PRSS1 , P07477 ); tryptase, a family of enzymes (α/β1 TPSAB1 , Q15661 ; γ1 TPSG1 , Q9NRR2 ; δ1 TPSD1 , Q9BZJ3 ) secreted from mast cells; cathepsin G ( CTSG , P08311 ) generated from leukocytes; liver-derived protein C ( PROC , P04070 ) generated in plasma by thrombin ( F2 , P00734 ) and matrix metalloproteinase 1 ( MMP1 , P45452 ).

G protein-coupled receptors → Melanin-concentrating hormone receptors Melanin-concentrating hormone (MCH) receptors ( provisional nomenclature as recommended by NC-IUPHAR [ 789 ]) are activated by an endogenous nonadecameric cyclic peptide identical in humans and rats (DFDMLRCMLGRVYRPCWQV; mammalian MCH) generated from a precursor ( PMCH , P20382 ), which also produces neuropeptide EI ( PMCH , P20382 ) and neuropeptide GE ( PMCH , P20382 ). The MCH 2 receptor appears to be a non-functional pseudogene in rodents [ 2781 ].

G protein-coupled receptors → Thyrotropin-releasing hormone receptors Thyrotropin-releasing hormone (TRH) receptors ( provisional nomenclature as recommended by NC-IUPHAR [ 789 ]) are activated by the endogenous tripeptide TRH ( TRH , P20396 ) (pGlu-His-ProNH2). TRH ( TRH , P20396 ) and TRH analogues fail to distinguish TRH 1 and TRH 2 receptors [ 2731 ]. [ 3 H]TRH ( human, mouse, rat ) is able to label both TRH 1 and TRH 2 receptors with K d values of 13 and 9 nM respectively. Synthesis and biology of ring-modified L-Histidine containing TRH analogues has been reported [ 1872 ].

G protein-coupled receptors → Corticotropin-releasing factor receptors Corticotropin-releasing factor (CRF, nomenclature as agreed by the NC-IUPHAR subcommittee on Corticotropin-releasing Factor Receptors [ 1068 ]) receptors are activated by the endogenous peptides corticotrophin-releasing hormone ( CRH , P06850 ), a 41 amino-acid peptide, urocortin 1 ( UCN , P55089 ), 40 amino-acids, urocortin 2 ( UCN2 , Q96RP3 ), 38 amino-acids and urocortin 3 ( UCN3 , Q969E3 ), 38 amino-acids. CRF 1 and CRF 2 receptors are activated non-selectively by CRH and UCN. CRF 2 receptors are selectively activated by UCN2 and UCN3. Binding to CRF receptors can be conducted using radioligands [ 125 I]Tyr 0 -CRF or [ 125 I]Tyr 0 -sauvagine with K d values of 0.1–0.4 nM. CRF 1 and CRF 2 receptors are non-selectively antagonized by α-helical CRF , D-Phe-CRF-(12–41) and astressin. CRF 1 receptors are selectively antagonized by small molecules NBI27914 , R121919 , antalarmin , CP 154,526 , CP 376,395 . CRF 2 receptors are selectively antagonized by antisauvagine and astressin 2B. Although selective small molecule CRF 1 receptor antagonists were not effective in treating major depressive disorder, posttraumatic stress disorder, or alcohol use disorder in clinical trials, recent phase 2 studies have found that CRF 1 receptor antagonists effectively reduce adrenocortical androgens and precursors in congentical adrenal hyperplasia [ 2059 ]. A CRF binding protein has been identified ( CRHBP , P24387 ) to which both corticotrophin-releasing hormone ( CRH , P06850 ) and urocortin 1 ( UCN , P55089 ) bind with high affinities, which has been suggested to bind and inactivate circulating corticotrophin-releasing hormone ( CRH , P06850 ) [ 591 , 2214 ].

G protein-coupled receptors → Gonadotrophin-releasing hormone receptors GnRH 1 and GnRH 2 receptors ( provisonal nomenclature [ 789 ], also called Type I and Type II GnRH receptor, respectively [ 1908 ]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [ 1907 , 1908 , 2614 ]. GnRH I ( GNRH1 , P01148 ) (p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) is a hypothalamic decapeptide also known as luteinizing hormone-releasing hormone, gonadoliberin, luliberin, gonadorelin or simply as GnRH. It is a member of a family of similar peptides found in many species [ 1907 , 1908 , 2614 ] including GnRH II ( GNRH2 , O43555 ) (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH 2 (which is also known as chicken GnRH-II). Receptors for three forms of GnRH exist in some species but only GnRH I and GnRH II and their cognate receptors have been found in mammals [ 1907 , 1908 , 2614 ]. GnRH 1 receptors are expressed by pituitary gonadotrophs, where they mediate the effects of GnRH on gonadotropin hormone synthesis and secretion that underpin central control of mammalian reproduction. GnRH analogues are used in assisted reproduction and to treat steroid hormone-dependent conditions [ 1393 ]. Notably, agonists cause desensitization of GnRH-stimulated gonadotropin secretion and the consequent reduction in circulating sex steroids is exploited to treat hormone-dependent cancers of the breast, ovary and prostate [ 1393 ]. GnRH 1 receptors are selectively activated by GnRH I and all lack the COOH-terminal tails found in other GPCRs. GnRH 2 receptors do have COOH-terminal tails and (where tested) are selective for GnRH II over GnRH I. GnRH 2 receptors are expressed by some primates but not by humans [ 1967 ]. Phylogenetic classifications divide GnRH receptors into three [ 1908 ] or five groups [ 3073 ] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene. The structure of the GnRH 1 receptor in complex with elagolix has been elucidated [ 3155 ]. Cryo-EM structures of GnRH bound to both pig and frog GnRHRs have also been reported [ 2583 ]. GnRH 1 and GnRH 2 receptors couple primarily to G q/11 [ 981 ] but coupling to G s and G i is evident in some systems [ 1504 , 1526 ]. GnRH 2 receptors may also mediate (heterotrimeric) G protein-independent signalling to protein kinases [ 399 ]. There is increasing evidence for expression of GnRH receptors on hormone-dependent cancer cells where they can exert antiproliferative and/or proapoptotic effects and mediate effects of cytotoxins conjugated to GnRH analogues [ 459 , 1056 , 1677 , 2502 ]. In some human cancer cell models GnRH II ( GNRH2 , O43555 ) is more potent than GnRH I ( GNRH1 , P01148 ), implying mediation by GnRH 2 receptors [ 984 ], but GnRH 2 receptors are not expressed by humans because the human GNRHR2 gene contains a frame shift and internal stop codon [ 1967 ]. The possibility remains that this gene generates GnRH 2 receptor-related proteins (other than the full-length receptor) that mediate responses to GnRH II ( GNRH2 , O43555 ) (see [ 2047 ]). Alternatively, evidence for multiple active GnRH receptor conformations [ 399 , 400 , 774 , 1847 , 1908 ] raises the possibility that GnRH 1 receptor-mediated proliferation inhibition in hormone-dependent cancer cells is dependent upon a conformation that couples to G i rather than G q/11 proteins as in pituitary cells [ 400 , 1847 ]. Loss-of-function mutations in the GnRH 1 receptor and deficiency of GnRH I ( GNRH1 , P01148 ) are associated with hypogonadotropic hypogonadism although some ‘loss of function’ mutations may actually prevent trafficking of ‘functional’ GnRH 1 receptors to the cell surface, as evidenced by recovery of function by nonpeptide antagonists [ 1593 ]. Human GnRH 1 receptors are poorly expressed at the cell surface because of failure to meet structural quality control criteria for endoplasmic reticulum exit [ 775 , 1593 ], and this increases susceptibility to point mutations that further impair trafficking [ 775 , 1593 ]. GnRH receptor signalling may require receptor oligomerisation [ 532 , 1502 ].