HVCN1 explained

Voltage-gated hydrogen channel 1 is a protein that in humans is encoded by the HVCN1 gene.

Voltage-gated hydrogen channel 1 is a voltage-gated proton channel that has been shown to allow proton transport into phagosomes^{[1] [2]} and out of many types of cells including spermatozoa, electrically excitable cells and respiratory epithelial cells.^[3] The proton-conducting HVCN1 channel has only transmembrane domains corresponding to the S1-S4 voltage sensing domains (VSD) of voltage-gated potassium channels and voltage-gated sodium channels.^[4] Molecular simulation is consistent with a water-filled pore that can function as a "water wire" for allowing hydrogen bonded H⁺ to cross the membrane.^{[5] [6]} However, mutation of Asp112 in human Hv1 results in anion permeation, suggesting that obligatory protonation of Asp produces proton selectivity.^[7] Quantum mechanical calculations show that the Asp-Arg interaction can produce proton selective permeation.^[8] The HVCN1 protein has been shown to exist as a dimer with two functioning pores.^{[9] [10]} Like other VSD channels, HVCN1 channels conduct ions about 1000-fold slower than channels formed by tetrameric S5-S6 central pores.^[11]

As a drug target

Small molecule inhibitors of the HVCN1 channel are being developed as chemotherapeutics and anti-inflammatory agents.^[12]

Further reading

• Li SJ, Zhao Q, Zhou Q, etal . The role and structure of the carboxyl-terminal domain of the human voltage-gated proton channel Hv1. . J. Biol. Chem. . 285 . 16 . 12047–54 . 2010 . 20147290 . 10.1074/jbc.M109.040360 . 2852942. free .
• Musset B, Smith SM, Rajan S, etal . Oligomerization of the voltage-gated proton channel. . Channels (Austin) . 4 . 4 . 260–5 . 2010. 20676047 . 10.4161/chan.4.4.12789. 3025757.
• Lishko PV, Botchkina IL, Fedorenko A, Kirichok Y . Acid extrusion from human spermatozoa is mediated by flagellar voltage-gated proton channel. . Cell . 140 . 3 . 327–37 . 2010 . 20144758 . 10.1016/j.cell.2009.12.053 . 7952753 . free .
• Kimura K, Wakamatsu A, Suzuki Y, etal . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. . Genome Res. . 16 . 1 . 55–65 . 2006 . 16344560 . 10.1101/gr.4039406 . 1356129.
• Musset B, Capasso M, Cherny VV, etal . Identification of Thr29 as a critical phosphorylation site that activates the human proton channel Hvcn1 in leukocytes. . J. Biol. Chem. . 285 . 8 . 5117–21 . 2010 . 20037153 . 10.1074/jbc.C109.082727 . 2820736. free .
• Petheo GL, Orient A, Baráth M, etal . Molecular and functional characterization of Hv1 proton channel in human granulocytes. . PLOS ONE . 5 . 11 . e14081 . 2010 . 21124855 . 10.1371/journal.pone.0014081 . 2990768. 2010PLoSO...514081P . free .
• Sasaki M, Takagi M, Okamura Y . A voltage sensor-domain protein is a voltage-gated proton channel. . Science . 312 . 5773 . 589–92 . 2006 . 16556803 . 10.1126/science.1122352 . 2006Sci...312..589S . 10259815 . free .
• Lee SY, Letts JA, Mackinnon R . Dimeric subunit stoichiometry of the human voltage-dependent proton channel Hv1. . Proc. Natl. Acad. Sci. U.S.A. . 105 . 22 . 7692–5 . 2008 . 18509058 . 10.1073/pnas.0803277105 . 2409406. 2008PNAS..105.7692L . free .
• Suzuki Y, Yamashita R, Shirota M, etal . Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions. . Genome Res. . 14 . 9 . 1711–8 . 2004 . 15342556 . 10.1101/gr.2435604 . 515316.
• Li SJ, Zhao Q, Zhou Q, Zhai Y . Expression, purification, crystallization and preliminary crystallographic study of the carboxyl-terminal domain of the human voltage-gated proton channel Hv1. . Acta Crystallographica Section F . 65 . Pt 3 . 279–81 . 2009 . 19255483 . 10.1107/S1744309109003777 . 2650464.
• Suenaga T, Arase H, Yamasaki S, etal . Cloning of B cell-specific membrane tetraspanning molecule BTS possessing B cell proliferation-inhibitory function. . Eur. J. Immunol. . 37 . 11 . 3197–207 . 2007 . 17948262 . 10.1002/eji.200737052 . 25376411 . free .
• Iovannisci D, Illek B, Fischer H . Function of the HVCN1 proton channel in airway epithelia and a naturally occurring mutation, M91T. . J. Gen. Physiol. . 136 . 1 . 35–46 . 2010 . 20548053 . 10.1085/jgp.200910379 . 2894549.
• Clark HF, Gurney AL, Abaya E, etal . The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. . Genome Res. . 13 . 10 . 2265–70 . 2003 . 12975309 . 10.1101/gr.1293003 . 403697.
• Musset B, Cherny VV, Morgan D, etal . Detailed comparison of expressed and native voltage-gated proton channel currents. . J. Physiol. . 586 . 10 . 2477–86 . 2008 . 18356202 . 10.1113/jphysiol.2007.149427 . 2464343.
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2002 . 12477932 . 10.1073/pnas.242603899 . 139241. 2002PNAS...9916899M . free .
• Ramsey IS, Moran MM, Chong JA, Clapham DE . A voltage-gated proton-selective channel lacking the pore domain. . Nature . 440 . 7088 . 1213–6 . 2006 . 16554753 . 10.1038/nature04700 . 4084761 . 2006Natur.440.1213R .
• Sakata S, Kurokawa T, Nørholm MH, etal . Functionality of the voltage-gated proton channel truncated in S4. . Proc. Natl. Acad. Sci. U.S.A. . 107 . 5 . 2313–8 . 2010 . 20018719 . 10.1073/pnas.0911868107 . 2836681. 2010PNAS..107.2313S . free .

Notes and References

1. Murphy R, DeCoursey TE . Charge compensation during the phagocyte respiratory burst . Biochim. Biophys. Acta . 1757 . 8 . 996–1011 . August 2006 . 16483534 . 10.1016/j.bbabio.2006.01.005 .
2. Capasso M, Bhamrah MK, Henley T, Boyd RS, Langlais C, Cain K, Dinsdale D, Pulford K, Khan M, Musset B, Cherny VV, Morgan D, Gascoyne RD, Vigorito E, DeCoursey TE, MacLennan IC, Dyer MJ . HVCN1 modulates BCR signal strength via regulation of BCR-dependent generation of reactive oxygen species . Nat. Immunol. . 11 . 3 . 265–72 . March 2010 . 20139987 . 3030552 . 10.1038/ni.1843 .
3. Capasso M, DeCoursey TE, Dyer MJ . pH regulation and beyond: unanticipated functions for the voltage-gated proton channel, HVCN1 . Trends Cell Biol. . 21 . 1 . 20–8 . January 2011 . 20961760 . 3014425 . 10.1016/j.tcb.2010.09.006 .
4. Lee SY, Letts JA, MacKinnon R . Functional reconstitution of purified human Hv1 H+ channels . J. Mol. Biol. . 387 . 5 . 1055–60 . April 2009 . 19233200 . 2778278 . 10.1016/j.jmb.2009.02.034 .
5. Wood ML, Schow EV, Freites JA, White SH, Tombola F, Tobias DJ . Water wires in atomistic models of the Hv1 proton channel . Biochim. Biophys. Acta . 1818 . 2 . 286–93 . February 2012 . 21843503 . 3245885 . 10.1016/j.bbamem.2011.07.045 .
6. Ramsey IS, Mokrab Y, Carvacho I, Sands ZA, Sansom MS, Clapham DE . An aqueous H+ permeation pathway in the voltage-gated proton channel Hv1 . Nat. Struct. Mol. Biol. . 17 . 7 . 869–75 . July 2010 . 20543828 . 10.1038/nsmb.1826 . 4035905.
7. Musset. B. Smith. SM. Rajan. S. Morgan. D. Cherny. VV. Decoursey. TE. Aspartate 112 is the selectivity filter of the human voltage-gated proton channel.. Nature. 23 October 2011. 480. 7376. 273–7. 22020278. 10.1038/nature10557. 3237871. 2011Natur.480..273M.
8. Dudev. T. Musset. B. Morgan. D. Cherny. VV. Smith. SM. Mazmanian. K. DeCoursey. TE. Lim. C. Selectivity Mechanism of the Voltage-gated Proton Channel, HV1.. Scientific Reports. 8 May 2015. 5. 10320. 25955978. 10.1038/srep10320. 4429351. 2015NatSR...510320D.
9. Gonzalez C, Koch HP, Drum BM, Larsson HP . Strong cooperativity between subunits in voltage-gated proton channels . Nat. Struct. Mol. Biol. . 17 . 1 . 51–6 . January 2010 . 20023639 . 2935852 . 10.1038/nsmb.1739 .
10. Tombola F, Ulbrich MH, Kohout SC, Isacoff EY . 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 . January 2010 . 20023640 . 2925041 . 10.1038/nsmb.1738 .
11. DeCoursey TE . Voltage-gated proton channels: what's next? . J. Physiol. . 586 . Pt 22 . 5305–24 . November 2008 . 18801839 . 2655391 . 10.1113/jphysiol.2008.161703 .
12. Hong L, Pathak MM, Kim IH, Ta D, Tombola F . Voltage-sensing domain of voltage-gated proton channel Hv1 shares mechanism of block with pore domains . Neuron . 77 . 2 . 274–87 . January 2013 . 23352164 . 3559007 . 10.1016/j.neuron.2012.11.013 .