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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).
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  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] .
* Key recommended reading is highlighted with an asterisk
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]
Database page citation:
Voltage-gated proton channel. Accessed on 09/02/2016. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=124.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Catterall WA, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA and CGTP Collaborators (2015) The Concise Guide to PHARMACOLOGY 2015/16: Voltage-gated ion channels. Br J Pharmacol. 172: 5904-5941.