Dissecting GPCR Selectivity: A complex interplay of various intracellular motifs determines G-protein binding and activation

2025 · doi:10.64898/2025.12.12.693856
preprint OA: closed
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This study investigated how structural motifs in the intracellular domains of muscarinic GPCRs govern both G-protein (Gα) binding selectivity and receptor activation. Using engineered chimeric receptors and FRET- and BRET-based assays to measure binding and activation, the authors found that coupling promiscuity or selectivity is not determined by any single motif or amino acid, but instead by a coordinated interplay of multiple intracellular motifs that differentially affect binding and/or subsequent activation. The main limitation is that the experiments focus on muscarinic receptors and the intracellular motif architecture they contain, leaving other GPCR families and additional regulatory contexts unaddressed. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

G-Protein coupled receptors (GPCRs) mediate intracellular signaling by selectively activating heterotrimeric G-proteins. While certain GPCRs exhibit a high specificity toward particular G-protein subtypes, other GPCRs display promiscuous signaling by engaging interaction with multiple G-protein families. Molecular determinants underlying the selectivity or promiscuity of the receptors remain incompletely understood. In the present study, we investigate various structural motifs within the intracellular domains of Muscarinic receptors to assess their role in both Gα subunit binding and activation. To this end, we generated chimeric receptors and applied both FRET- and BRET-based assays to monitor G protein binding and activation. Our study demonstrates that the determination of G-protein coupling selectivity is not defined by single motifs or amino acids but rather by a complex interplay of various intracellular motifs affecting binding or/and subsequent activation. These results provide new insights into the structural basis of GPCR-G protein specificity.
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Abstract G-Protein coupled receptors (GPCRs) mediate intracellular signaling by selectively activating heterotrimeric G-proteins. While certain GPCRs exhibit a high specificity toward particular G-protein subtypes, other GPCRs display promiscuous signaling by engaging interaction with multiple G-protein families. Molecular determinants underlying the selectivity or promiscuity of the receptors remain incompletely understood. In the present study, we investigate various structural motifs within the intracellular domains of Muscarinic receptors to assess their role in both Gα subunit binding and activation. To this end, we generated chimeric receptors and applied both FRET- and BRET-based assays to monitor G protein binding and activation. Our study demonstrates that the determination of G-protein coupling selectivity is not defined by single motifs or amino acids but rather by a complex interplay of various intracellular motifs affecting binding or/and subsequent activation. These results provide new insights into the structural basis of GPCR-G protein specificity. Competing Interest Statement The authors have declared no competing interest.

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last seen: 2026-05-20T01:45:00.602351+00:00