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 [1-3,12,14]. 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 [12,14]. Proton flux through Hv1 is instead most likely mediated by a water wire completed in a crevice of the protein when the voltage-sensing S4 helix moves in response to a change in transmembrane potential [11,17]. Hv1 expresses largely as a dimer mediated by intracellular C-terminal coiled-coil interactions [7] but individual promoters nonetheless support gated H+ flux via separate conduction pathways [5-6,10,15]. 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 [4,16] .
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Subunits 
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Capasso, M; DeCoursey, TE; Dyer, MJ. (2011) pH regulation and beyond: unanticipated functions for the voltage-gated proton channel, HVCN1. Trends Cell Biol., 21 (1): 20-8. [PMID:20961760]
DeCoursey, TE. (2008) Voltage-gated proton channels. Cell. Mol. Life Sci., 65 (16): 2554-73. [PMID:18463791]
DeCoursey, TE. (2008) Voltage-gated proton channels: what's next?. J. Physiol. (Lond.), 586 (Pt 22): 5305-24. [PMID:18801839]
DeCoursey, TE; Cherny, VV. (2007) Pharmacology of voltage-gated proton channels. Curr. Pharm. Des., 13 (23): 2400-20. [PMID:17692009]
Tombola, F; Ulbrich, MH; Isacoff, EY. (2009) Architecture and gating of Hv1 proton channels. J. Physiol. (Lond.), 587 (Pt 22): 5325-9. [PMID:19915215]
1. Capasso, M; DeCoursey, TE; Dyer, MJ. (2011) pH regulation and beyond: unanticipated functions for the voltage-gated proton channel, HVCN1. Trends Cell Biol., 21 (1): 20-8. [PMID:20961760]
2. DeCoursey, TE. (2008) Voltage-gated proton channels. Cell. Mol. Life Sci., 65 (16): 2554-73. [PMID:18463791]
3. DeCoursey, TE. (2008) Voltage-gated proton channels: what's next?. J. Physiol. (Lond.), 586 (Pt 22): 5305-24. [PMID:18801839]
4. Gonzalez, C; Koch, HP; Drum, BM; Larsson, HP. (2010) Strong cooperativity between subunits in voltage-gated proton channels. Nat. Struct. Mol. Biol., 17 (1): 51-6. [PMID:20023639]
5. Koch, HP; Kurokawa, T; Okochi, Y; Sasaki, M; Okamura, Y; Larsson, HP. (2008) Multimeric nature of voltage-gated proton channels. Proc. Natl. Acad. Sci. U.S.A., 105 (26): 9111-6. [PMID:18583477]
6. Lee, SY; Letts, JA; Mackinnon, R. (2008) Dimeric subunit stoichiometry of the human voltage-dependent proton channel Hv1. Proc. Natl. Acad. Sci. U.S.A., 105 (22): 7692-5. [PMID:18509058]
7. Li, SJ; Zhao, Q; Zhou, Q; Unno, H; Zhai, Y; Sun, F. (2010) The role and structure of the carboxyl-terminal domain of the human voltage-gated proton channel Hv1. J. Biol. Chem., 285 (16): 12047-54. [PMID:20147290]
8. Musset, B; Capasso, M; Cherny, VV; Morgan, D; Bhamrah, M; Dyer, MJ; DeCoursey, TE. (2010) Identification of Thr29 as a critical phosphorylation site that activates the human proton channel Hvcn1 in leukocytes. J. Biol. Chem., 285 (8): 5117-21. [PMID:20037153]
9. Musset, B; Smith, SM; Rajan, S; Cherny, VV; Sujai, S; Morgan, D; DeCoursey, TE. (2010) Zinc inhibition of monomeric and dimeric proton channels suggests cooperative gating. J. Physiol. (Lond.), 588 (Pt 9): 1435-49. [PMID:20231140]
10. Petheo, GL; Orient, A; Baráth, M; Kovács, I; Réthi, B; Lányi, A; Rajki, A; Rajnavölgyi, E; Geiszt, M. (2010) Molecular and functional characterization of Hv1 proton channel in human granulocytes. PLoS ONE, 5 (11): e14081. [PMID:21124855]
11. Ramsey, IS; Mokrab, Y; Carvacho, I; Sands, ZA; Sansom, MS; Clapham, DE. (2010) An aqueous H+ permeation pathway in the voltage-gated proton channel Hv1. Nat. Struct. Mol. Biol., 17 (7): 869-75. [PMID:20543828]
12. Ramsey, IS; Moran, MM; Chong, JA; Clapham, DE. (2006) A voltage-gated proton-selective channel lacking the pore domain. Nature, 440 (7088): 1213-6. [PMID:16554753]
13. Ramsey, IS; Ruchti, E; Kaczmarek, JS; Clapham, DE. (2009) Hv1 proton channels are required for high-level NADPH oxidase-dependent superoxide production during the phagocyte respiratory burst. Proc. Natl. Acad. Sci. U.S.A., 106 (18): 7642-7. [PMID:19372380]
14. Sasaki, M; Takagi, M; Okamura, Y. (2006) A voltage sensor-domain protein is a voltage-gated proton channel. Science, 312 (5773): 589-92. [PMID:16556803]
15. Tombola, F; Ulbrich, MH; Isacoff, EY. (2008) The voltage-gated proton channel Hv1 has two pores, each controlled by one voltage sensor. Neuron, 58 (4): 546-56. [PMID:18498736]
16. Tombola, F; Ulbrich, MH; Kohout, SC; Isacoff, EY. (2010) The opening of the two pores of the Hv1 voltage-gated proton channel is tuned by cooperativity. Nat. Struct. Mol. Biol., 17 (1): 44-50. [PMID:20023640]
17. Wood, ML; Schow, EV; Freites, JA; White, SH; Tombola, F; Tobias, DJ. (2011) Water wires in atomistic models of the Hv1 proton channel. Biochim Biophys Acta, [Epub ahead of print]. [PMID:21843503]
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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]. Phosphorylation of Hv1 within the N-terminal domain by PKC enhances the gating of the channel [8]. Tabulated IC50 values for Zn2+ and Cd2+ are for heterologously expressed human and mouse Hv1 [12,14]. Zn2+ is not a conventional pore blocker, but is coordinated by two, or more, external protonation sites involving histamine residues [12]. Zn2+ binding may occur at the dimer interface between pairs of histamine residues from both monomers where it may interfere with channel opening [9]. Mouse knockout studies demonstrate that Hv1 participates in charge compensation in granulocytes during the respiratory burst of NADPH oxidase-dependent reactive oxygen species production that assists in the clearance of bacterial pathogens [13]. Additional physiological functions of Hv1 are reviewed by [1].