Modulators of the human voltage-gated proton channel Hv1

Modulators of the human voltage-gated proton channel Hv1 | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 18 June 2025 V1 Latest version Share on Modulators of the human voltage-gated proton channel Hv1 Authors : Jesus Angel Borrego Terrazas , Beáta Mészáros , Gabor Tibor Szanto , Teklu Teshome Russo , Éva Korpos , Zoltan Varga , and Ferenc Papp 0000-0002-9549-6066 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175023587.77488082/v1 349 views 135 downloads Contents Abstract ABSTRACT Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract not-yet-known not-yet-known not-yet-known unknown The voltage-gated proton channel (Hv1) selectively transports protons (H⁺) across biological membranes in response to membrane potential changes. Hv1 assembles as a dimer and unlike most voltage-gated ion channels, it lacks a traditional central pore domain; instead, the voltage-sensing domain (VSD) of each monomer facilitates proton conduction via a hydrogen bond network. Hv1 is widely expressed in various human cell types (e.g., immune cells, sperm, etc.) including tumor cells. In tumor cells, the accumulation of acidic intermediates generated by glycolysis under hypoxic conditions or ROS production leads to significant cytosolic acidification. Hv1 can remove protons from the cytosol rapidly, contributing to the adaptation of the cells to the tumor microenvironment, which may have significant consequences in tumor cell survival, proliferation and progression. Therefore, Hv1 may be very promising not only as a tumor marker but also as a potential therapeutic target in oncology. Molecules that modulate the proton flux through Hv1 can be divided into two broad groups: inhibitors and activators. Hv1 inhibitors can be simple ions, small molecules, lipids, and peptides. In contrast, fewer Hv1 activators are known, including Albumin, NH29, Quercetin, and arachidonic acid. The mechanism of action of some inhibitors is well described, but not all. Hv1 modulation has profound effects on cellular physiology, especially under stress or pathological conditions, like cancer and inflammation. The therapeutic application of selective Hv1 inhibitors or activators could be a very promising strategy in the treatment of several serious diseases. Modulators of the human voltage-gated proton channel Hv1 Jesús Borrego 1x , Beáta Mészáros 1x , Szanto Gabor Tibor 1 , Russo Teklu Teshome 1 , Éva Korpos 1,2 , Zoltan Varga 1 , and Ferenc Papp 1* Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, Debrecen H-4032, Hungary MTA-DE Cell Biology and Signalling Research Group, Faculty of Medicine, University of Debrecen, Hungary * Correspondence should be addressed to F.P. ( [email protected] ) X These authors contributed equally to this work. Running Title: Modulators of Hv1 Keywords: Peptide inhibitors, small molecule inhibitors, Hv1 activators, human Hv1 Conflicts of Interest: The authors state that there is no conflicts of Interest. ABSTRACT The voltage-gated proton channel (Hv1) selectively transports protons (H⁺) across biological membranes in response to membrane potential changes. Hv1 assembles as a dimer and unlike most voltage-gated ion channels, it lacks a traditional central pore domain; instead, the voltage-sensing domain (VSD) of each monomer facilitates proton conduction via a hydrogen bond network. Hv1 is widely expressed in various human cell types (e.g., immune cells, sperm, etc.) including tumor cells. In tumor cells, the accumulation of acidic intermediates generated by glycolysis under hypoxic conditions or ROS production leads to significant cytosolic acidification. Hv1 can remove protons from the cytosol rapidly, contributing to the adaptation of the cells to the tumor microenvironment, which may have significant consequences in tumor cell survival, proliferation and progression. Therefore, Hv1 may be very promising not only as a tumor marker but also as a potential therapeutic target in oncology. Molecules that modulate the proton flux through Hv1 can be divided into two broad groups: inhibitors and activators. Hv1 inhibitors can be simple ions, small molecules, lipids, and peptides. In contrast, fewer Hv1 activators are known, including Albumin, NH29, Quercetin, and arachidonic acid. The mechanism of action of some inhibitors is well described, but not all. Hv1 modulation has profound effects on cellular physiology, especially under stress or pathological conditions, like cancer and inflammation. The therapeutic application of selective Hv1 inhibitors or activators could be a very promising strategy in the treatment of several serious diseases. Introduction Voltage-gated Proton Channels Voltage-gated proton channels (Hv) represent a unique family of voltage-gated ion channels responsible for the selective passage of protons (H⁺) across biological membranes in response to changes in membrane potential. The first direct electrophysiological evidence of voltage-gated and pH-sensitive proton currents was published in the early 1980s [1]. This pioneering study laid the groundwork for understanding voltage-gated proton channels, whose molecular was later identified in 2006 [2, 3]. The voltage-sensing domain (VSD) of Hv channels serves the dual function of sensing voltage changes and facilitating proton permeation [4]. Recently our understanding of the voltage-gated proton channel family has been expanded with the discovery and characterization of three new proton channel members: AcHv1, AcHv2, and AcHv3 identified in the mollusc ”Aplysia californica” [5]. More recently, another Hv channel was announced, namely Hv4, which was identified only in Bivalvian molluscs [6]. Hv1 shows a wide tissue distribution pattern and presents diverse functions. It is expressed by several cell types in physiological conditions like different immune cell types (neutrophils [7], eosinophils [8], macrophages [9], microglia [10], T- and B-cells [11, 12]), human airway epithelium cells [13], human cardiac fibroblast [14], chorion-derived mesenchymal stem cells [15], pancreatic islet β-cells [16] sperm [17], oocyte [18]. Hv1 is also expressed in pathological situation, such as by tumor cells: malignant B-cells [19], glioblastoma multiforme cells [20], leukemic Jurkat T cells [21], breast-cancer cells [22, 23] , colorectal cancer cell lines [24] . Structure of Hv1 Structurally, Hv channels differ from classic voltage-gated ion channels (VGIC), such as sodium (Nav), potassium (Kv), or calcium (Cav) ion channels. Typically, VGICs are composed of either homo- or heterotetrameric structures (Kv) or a single polypeptide chain of four homologous domains (Nav and Cav); each of the four subunits or domains consists of six transmembrane α-helical segments linked by intra- and extracellular loops. Of these, segments S1-S4 form the voltage-sensing domain (VSD) that regulates channel opening upon membrane depolarization, while segments S5-S6 and the connecting extracellular pore-loops (P-loops) constitute the pore domain. However, Hv channels have a unique architecture, as they are homodimers, composed of only two identical subunits, and both subunits contain four transmembrane segments (S1-S4) serving as VSDs ( Figure 1 ). Unlike most VGICs, there is no distinct pore structure in Hv1 channels. Instead, protons permeate through each VSD individually, with each monomer acting as an independent and isolated VSD, each with its intrinsic conduction pathway. [25] More specifically proton conduction in Hv1 channels may be described by the Grotthus mechanism, that is, H+ ions are hopping along a robust water wire within the channel structure, facilitated by specific water–protein interactions [26]. The S4 segment terminates with a coiled-coil region facing the cell interior ( Figure 3 ), which contributes to the dimerization of the channel [27]. The voltage and pH-gated proton channels are highly selective for H + ions ensured by specific charged residues: the open Hv1 channel requires an aspartate at 112 (D112) in the S1 segment and an arginine at 211 (R211) in the S4 helix forming a narrow region that conducts protons selectively [28]. The voltage-sensing part of the channel contains three positively charged arginine residues, known as gating arginines (R205, R208, and R211); all are located in the S4 domain. These gating arginines interact with their negatively charged countercharge-residues in the S1-S3 domains and “detect” the change in the membrane potential [29]. When the cell membrane is depolarized, or when there is an elevated proton concentration in the cyctosol or on the contrary, the extracellular pH is alkaline, they trigger channel activation [30]. In Hv1 channels, there is no inactivation mechanism, only open or closed states are observed [31]. In response to membrane depolarization, the gating arginines are repelled toward the extracellular space. This movement modifies the salt bridge interactions between the positively charged arginines in S4 and their countercharges in S1-S3, shifting the S4 domain towards the extracellular space. These changes are mediated by two steps, as described by the simplest, 3-state model based on Hv1 current and fluorescence recordings [32, 33]. According to this model, the structural changes between the different states result in a notable shift in the salt-bridge interaction network formed between S3 and S4. Changes upon channel activation critically affect the permeability and water distribution: internal water molecules interact with charged residues via hydrogen bonds suggesting that in the open state, the channel permits protons from the cytosol to the extracellular space by conducting them through an extended hydrogen bond network formed between water molecules and acidic amino acid side chains. [26] Functions of Hv1 and its role in cancer Studies have revealed the diverse roles of Hv1 in these cell types: the ability of rapid and robust protons transport from the cytosol, thus regulating the intracellular (IC) pH of cells. Therefore, Hv1 is involved in many processes that can lead to decrease in IC pH, such as the NADPH oxidase-dependent production of ROS by immune cells [34] or the accumulation of acidic intermediates during glycolysis in tumor cells under hypoxic conditions [35]. However, in many cases the role of Hv1 in different cellular processes has not yet been clarified. Without being exhaustive, the role of Hv1 has been highlighted in cancer cell migration and proliferation, cell survival and apoptosis [10, 21], sustained calcium entry [36], neutrophil migration and superoxide production [36], sperm capacitation and motility [17], participation in optimal B-cell receptor signaling and redox control in human B lymphocytes [19], regulation of insulin secretion [16]. Moreover, Hv1 plays a crucial role in cancer development, progression, and metastasis formation, allowing Hv1 to become a potential target in tumor therapy [23]. During processes producing ROS or under hypoxic conditions, tumor cells produce elevated proton concentration in the cytosol. When IC pH reaches a critical value relative to the extracellular pH, the threshold potential for channel opening of Hv1 shifts sufficiently towards a more negative membrane potential releasing protons from the cell, thereby reducing the proton concentration in the cytosol. If, however, the Hv1 channel is inhibited, IC pH in tumor cells is expected to remain permanently low promoting cell death (Figure 2). Hv1 may also be important in the normal function and regulation of nervous system, and accordingly, Hv1 can be responsible for various neurological diseases [37]. Thus, finding or developing a suitable Hv1 inhibitor or activator has been intensively pursued. Functional studies have explored a number of known Hv1 inhibitors or activators, but for most of these, selectivity (whether they affect other ion channels) has not been investigated. Hv1 inhibition by Zn 2+ or ClGBI produced a significant acidification of Jurkat cells and induced cell death by apoptosis [21]. ClGBI also decreased the cell viability of tumorigenic breast cells along with a decrease of IC pH [22]. Inhibiting Hv1 with Zn 2+ significantly reduced the IC pH, decreasing cell survival and migration of a glioblastoma multiforme cell line [20]. Moreover, Zn 2+ markedly decreased the cell invasion and migration of a colorectal cell line (SW620, HT29; [24]), as well. Zn 2+ ions also induced apoptosis in human highly metastatic glioma and effectively suppressed cancer growth and metastasis by reducing proton extrusion and downregulating gelatinase activity [38]. Myeloid-derived suppressor cells (MDSC) also express Hv1 [39]. ClGBI significantly decreased the migration and osteogenic differentiation of chorion-derived mesenchymal stem cells [15]. Corza6 blocked the acrosome reaction during capacitation of sperm and inhibited ROS production in human WBC [40], as well. Inhibition of neuronal Hv1 by a newly discovered inhibitor YHV98-4 reduced intracellular alkalization and ROS production in peripheral sensory neurons [41]. Interestingly, macrophages are an important source of arachidonic acid metabolites, which are able to activate Hv1 [42]. Since the inhibitors are not selective for Hv1, it is difficult to estimate how much of these effects are due to the inhibition of proton currents or due to other reasons. Recently it has been shown that ClGBI is not a specific inhibitor of Hv1 since it inhibits several other channels [43] on lymphocytes. 2GBI, the precursor of ClGBI has been shown to bind to NLRP3, which leads to inflammasome assembly and activation. This function of 2GBI is independent of Hv1, since the impact on inflammasome is also detected in bone marrow derived macrophages where HVCN1gene was knocked down [44]. Therefore, the use of Hv1 knock out (KO) mice or silencing HVCN1 gene is needed additional to pharmacological studies to understand and explore the function of Hv1 in health and disease [23, 45] [46] [24, 39]. Targeting Hv1 proton channel in biological systems is pretty challenging due to its broad tissue distribution pattern. While considering Hv1 as a potential target in cancer therapy, it has to be taken into consideration that Hv1 is also expressed by immune cells that present anti-cancer properties such as cytotoxic T-cells and B-cells. Figure 2. Schematic representation of how Hv1 inhibition is responsible for promoting cell death by preventing proton extrusion. (top) The normal mechanism for sustained ROS production or hypoxia elevates intracellular H+ and the action of Hv1 compensates for the accumulation of H+. (bottom) When Hv1 is inhibited, the accumulation of protons and consequent lowering of pH inhibits the action of NOX2, which in turn reduces the production of ROS maintaining the intracellular acidification that promotes cell death. Hv1 modulators The proton current through the Hv1 channel can be modulated by a diverse array of molecules at concentrations ranging from nanomolar (nM) to micromolar (µM) levels (Table 1). These Hv1 modulators are simple ions (e.g. Zn 2+ ), small molecules (e.g., HIF, ClGBI), unsaturated fatty acids (e.g., arachidonic acid), and peptides (e.g., HaTx, GsAF-I). Based on their mechanisms of action, the Hv1 modulators can be divided into two groups: inhibitors and activators. Compound Type IC 50 Effect on the channel Reference 13 Small molecule 8.5 µM Inhibitor [47] 2GBI Small molecule 38 µM Inhibitor [48] AGAP/W38F Peptide 2.5 µM Inhibitor [49] Cd 2+ Cation 5 µM Inhibitor [50] Chlorpromazine Small molecule 2.2 µM Inhibitor [51] Cholesterol Lipid ∼10% (wt/wt, to total membrane lipids) Inhibitor [52] ClGBI Small molecule 26.3 µM Inhibitor [53] Clozapine Small molecule 9.8 µM Inhibitor [54] Desipramine Small molecule <10 µM Inhibitor [55] Dextromethorphan Small molecule 51.7 µM Inhibitor [56] Epigallocatechin Small molecule 3.7 µM Inhibitor [57] Fluoxetine Small molecule 2.1 µM Inhibitor [55] Gr1b/GsAF-l Peptide 3.2 µM Inhibitor —– Gr2c/GsAF-ll Peptide 3.6 µM Inhibitor —– Haloperidol Small molecule 8.4 µM Inhibitor [51] Hanatoxin Peptide 2 µM Inhibitor [58] HIF Small molecule 26 µM Inhibitor [59] Imipramine Small molecule 5.7 µM Inhibitor [55] Mitriptyline Small molecule 5.8 µM Inhibitor [55] NH17 Small molecule >50 µM Inhibitor [60] Olanzapine Small molecule 84 µM Inhibitor [54] Oxopench Small molecule 819 nM Inhibitor [61] Peptide C6 Peptide 31 nM Inhibitor [62] PNX52429 Small molecule >50 µM Inhibitor [63] PNX61442 Small molecule 50 µM Inhibitor [63] YHV98-4 Small molecule 700 nM Inhibitor [41] Zn +2 Cation 5.7 µM Inhibitor [50] Albumin Protein 158 µM Activator [64] Arachidonic acid Lipid 10-100 µM Activator [42] NH29 Small molecule 50 µM Activator [60] OPE (Onion peel extract) Organic extract 30 µg/ml Activator [65] Hv1 inhibitors One of the earliest identified inhibitors of Hv1 was Zn 2+ [66]. This divalent cation inhibits Hv1 in a reversible manner by binding to the closed conformation of Hv1, thereby reducing the open probability of the channel and stabilizing its non-conducting state [67]. The binding site of Zn 2+ is in the S3-S4 loop, with H140 and H193 playing key roles in binding [30, 68]. In addition to Zn 2+ , several other inhibitors exhibit a similar mechanism of action. For instance, the mutated version of AGAP-W38F (anti-tumor analgesic peptide), isolated from the scorpion Buthus martensii , behaves as an Hv1 inhibitor by trapping the S4 voltage sensor in its deactivated state [49]. In contrast, while Zn 2+ inhibition demonstrates a high degree of pH dependency, AGAP exhibits a reduced sensitivity to pH changes. Intriguingly, the binding pocket of AGAP-W38F partially overlaps with that of Zn 2+ , sharing critical residues H140 and H193 [49]. Other molecules that also stabilize the channel at its closed conformation are cholesterol [52], Oxophench [61], PNX61442 [63], molecule called 13 [47], and NH17 [60]; however, the molecular determinants underlying their interaction with Hv1 is still poorly understood. Molecules derived from guanidine have also been identified as Hv1 inhibitors [53]. 2-Guanidinobenzimidazole ( 2GBI ) has been observed to bind to the voltage-sensing domain (VSD) when the channel is in its open conformation. The binding pocket, accessible from the intracellular side of the membrane, involves amino acids D112, F150, S181, and R211, with F150 being critical for the interaction [53, 69]. However, due to its high polarity, 2GBI has low permeability through cell membranes, therefore limiting its usage in pharmacological studies and precluding it from being a drug candidate [48, 70]. To address this limitation, a derivative called Cl-guanidinobenzimidazole ( ClGBI ) was developed, that exhibits enhanced membrane permeability, enabling access to the intracellular domain of the channel and blocking it with higher binding affinity [53]. However, ClGBI has been shown to inhibit not only Hv1 at micromolar concentrations, but also other ion channels, which greatly limits its future use as a tool in functional studies or as a potential drug candidate [43]. Another small molecule derivative, HIF (3-(2-amino-5-methyl-1H-imidazol-4-yl)-1-(3,5-difluorophenyl)propan-1-one), exhibits dual mechanisms of action depending on its interaction site within the channel. When HIF binds to “site 1”, its binding mechanism is similar to 2GBI, and it was confirmed that mutations of D112 and F150 abolish the inhibitory effect of HIF against Hv1. In contrast, binding to “site 2”, involving residues E171 and D174, leads to a slower recovery from inhibition [59]. Located near the 2GBI pocket, another binding pocket has been identified that accommodates the small molecule modulator of YHV98-4 . This pocket is formed by amino acids I155, F161, and S219. Molecular dynamics (MD) simulations suggest that upon binding to Hv1, YHV98-4 inhibits proton conduction by disrupting the water wires necessary for proton transfer [41]. Certain antidepressant drugs e.g., imipramine [55], antitussive drugs, e.g., dextromethorphan [56], and antipsychotic drugs, such as chlorpromazine , haloperidol , and clozapine [51, 54], have been shown to inhibit the voltage-gated proton currents in BV2 microglial cells. These drugs penetrate the cell membrane in their uncharged, neutral form, and subsequently undergo protonation in the cytosol. The charged forms of the drugs then block the proton channel intracellularly. Since these molecules are protonated, they may reduce the pH gradient potentially leading to the reduction of the proton current. However, no changes in the reversal potential of the current were observed, suggesting that the inhibition mechanism does not directly alter the electrochemical equilibrium. Moreover, a similar inhibitory effect has been reported for other molecules, such as epigallocatechin-3-gallate (EGCG), the principal bioactive constituent of green tea [57]. Further studies are needed to fully explore the mechanism by which these protonated molecules inhibit proton currents. Besides the peptide inhibitor AGAP-W38F, other peptides have also been reported as Hv1 inhibitors. One of these is the synthetic C6 peptide, which binds with nanomolar affinity to both S3-S4 loops of the dimer hHv1 in a cooperative manner. This cooperative binding causes the C6-bound channels to activate at a more positive membrane potential, i.e., C6 slows the activation of Hv1. The most critical residues for this interaction are V187, E192, H193, E196, and L200 [62]. The venom of the tarantula Grammostola rosea has also been identified as the source of three Hv1 inhibitors. The first of these is Hanatoxin (HaTx), one of the earliest reported peptides that is capable of inhibiting Hv1. Extracellular application of HaTx produced inhibition of Hv1 proton currents, shifting the activation of the channel to more positive voltages [58]. Based on the interaction with Kv1.2, HaTx is assumed to partition into the membrane before interacting with a binding site at the protein-lipid interface. D185 plays a key role in this interaction, as shown by site-directed mutagenesis (D185A) that effectively abolished the inhibitory effect of HaTx [58]. The other two peptides isolated from Grammostola rosea, Gr1b ( GsAF-I ) and Gr2c ( GsAF-II ), showed similar effects to HaTx; they shifted the activation threshold potential of Hv1 towards more positive potentials, reduced the Hv1 current in a membrane potential-dependent manner, and stabilized the channel in its closed state (reference). However, the molecular determinants responsible for these inhibitory effects are still unknown. not-yet-known not-yet-known not-yet-known unknown Hv1 activators. not-yet-known not-yet-known not-yet-known unknown In contrast to the Hv1 inhibitors, only a few Hv1 activators have been described so far. One notable example is albumin (Alb), which has been shown to enhance the open probability and increase proton currents in Hv1. A single Alb molecule binds to the dimeric hHv1 channel at both voltage-sensor domains (VSDs), specifically to the external S3-S4 loops. Mutations H193C and L200C in Hv1 fully eliminated Alb activation, suggesting that these two residues mediate direct interaction with Alb [64]. Interestingly, these residues are also involved in the inhibitory effects of Zn²⁺ and C6 peptide. Similar to Alb, NH29 stabilizes the Hv1 channel in its open state [60]. External application of NH29 increased proton currents at all test potentials, primarily due to a significant hyperpolarizing shift in the conductance-voltage relationship [60]. Another activator, onion peel extract (OPE ) from Allium cepa L., was found to modulate Hv1 channel opening and activates the channel at more negative membrane voltages. Subsequent studies revealed that quercetin, the major active component in OPE, is responsible for this effect. The activation of Hv1 induced by OPE was inhibited by 10 µM Zn²⁺ and GF109203X (GFX), a specific protein kinase C (PKC) inhibitor. It was concluded that the pro-oxidant effects of quercetin play a significant role in OPE-induced activation of Hv1 as well as its probable involvement in PKC signaling pathways [65]. While the precise interaction between OPE, PKC, and Hv1 remains unclear, similar PKC-related mechanisms have been observed in Hv1 activation by lipopolysaccharide (LPS). The acute addition of LPS increased Hv1 channel activity, that was abolished by GFX. However, the activating effect of LPS on Hv1 disappeared after 24 hours incubation with LPS, instead acting as an inhibitor compound over time [71]. Previously, it was thought that arachidonic acid (AA) required Hv1 phosphorylation to activate the channel. However, in the shorter isoform of mHv1 lacking the N-terminus, where the phosphorylation site T29 is located, Hv1 current increased after AA addition. It was concluded that AA acts on mHv1 after incorporating into the membrane, rather than directly targeting the channel from the extracellular side of the membrane. The hydrophilic head group of AA is essential for its effect, whereas charge does not seem to play a critical role [42]. Figure 1 shows the most important binding sites for activators and inhibitors, while Figure 3 shows the mechanism of their action with the Hv1 channel. Hv1 has emerged as a pivotal player in numerous physiological and pathological contexts, particularly in cancer and inflammation. The growing repertoire of Hv1 modulators not only deepens our understanding of proton channel function but also opens the door to promising therapeutic strategies. Targeting Hv1 with selective modulators may soon translate into meaningful advances in disease treatment. not-yet-known not-yet-known not-yet-known unknown References 1. Thomas, R.C. and R.W. 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Authors Affiliations Jesus Angel Borrego Terrazas University of Debrecen Department of Biophysics and Cell Biology View all articles by this author Beáta Mészáros 1 Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, View all articles by this author Gabor Tibor Szanto 1 Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen View all articles by this author Teklu Teshome Russo University of Debrecen Department of Biophysics and Cell Biology View all articles by this author Éva Korpos 1 Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen View all articles by this author Zoltan Varga University of Debrecen View all articles by this author Ferenc Papp 0000-0002-9549-6066 [email protected] 1 Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, View all articles by this author Metrics & Citations Metrics Article Usage 349 views 135 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Jesus Angel Borrego Terrazas, Beáta Mészáros, Gabor Tibor Szanto, et al. 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