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Voltage-gated proton channel (Hv1) C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
The voltage-gated proton channel (provisionally denoted Hv1) is a putative 4TM proton-selective channel gated by membrane depolarization and which is sensitive to the transmembrane pH gradient [1,5-6,29,31]. The structure of Hv1 is homologous to the voltage-sensing domain (VSD) of the superfamily of voltage-gated ion channels (i.e. segments S1 to S4) and contains no discernable pore region [29,31]. Proton flux through Hv1 is instead most likely mediated by a hydrogen-bonded chain [4,25] formed in a crevice of the protein when the voltage-sensing S4 helix moves in response to a change in transmembrane potential [28,37]. Proton selective conduction requires an aspartate residue at the center of the pore [2,24,33]. Both selectivity and conduction may result from obligatory protonation by each conducted proton [8,11]. Hv1 expresses largely as a dimer mediated by intracellular C-terminal coiled-coil interactions [19] but individual promoters nonetheless support gated H+ flux via separate conduction pathways [17-18,26,34]. Within dimeric structures, the two protomers do not function independently, but display co-operative interactions during gating resulting in increased voltage sensitivity, but slower activation, of the dimeric, versus monomeric, complexes [13,35]. The otopetrin proteins appear to form proton-selective ion channels and to date 3 subtypes have been identified in eukaryotes; otopetrin 1 [27,36], otopetrin 2 [20] and otopetrin 3 [15].
Channels and Subunits
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Hv1 C Show summary » |
Comments
Further reading
How to cite this family page
Database page citation:
Voltage-gated proton channel (Hv1). Accessed on 08/04/2026. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=124.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Striessnig J, Gibb AJ, Mathie AA, Veale EL, Kelly E, Peach CJ, Armstrong JF, Faccenda E, Harding SD, Southan C, Davies JA et al. (2025) The Concise Guide to PHARMACOLOGY 2025/26: Ion channels. Br J Pharmacol. 182: S152-S241.
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The voltage threshold (Vthr) for activation of Hv1 is not fixed but is set by the pH gradient across the membrane such that Vthr is positive to the Nernst potential for H+, which ensures that only outwardly directed flux of H+ occurs under physiological conditions [1,3,5-6]. Phosphorylation of Hv1 within the N-terminal domain by PKC enhances the gating of the channel [7,9,22]. Tabulated IC50 values for Zn2+ and Cd2+ are for heterologously expressed human and mouse Hv1 [29,31]. Zn2+ is not a conventional pore blocker, but is coordinated by two, or more, external protonation sites involving histamine residues [29]. Zn2+ binding may occur at the dimer interface between pairs of histamine residues from both monomers where it may interfere with channel opening [23]. Mouse knockout studies [12,21,30] support the view that Hv1 participates in both charge compensation and pH regulation in granulocytes during the respiratory burst of NADPH oxidase-dependent reactive oxygen species production that assists in the clearance of bacterial pathogens [10,14,16,32]. Additional physiological functions of Hv1 are reviewed by [1].