HVCN1

Hydrogen voltage gated channel 1

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
3A2A

Identifiers

Symbols

HVCN1 ; HV1; VSOP

External IDs

OMIM: 611227 MGI: 1921346 HomoloGene: 12535 IUPHAR: 746 GeneCards: HVCN1 Gene

Gene ontology
Molecular function	• voltage-gated cation channel activity • voltage-gated proton channel activity
Cellular component	• plasma membrane • integral component of plasma membrane • integral component of membrane
Biological process	• single fertilization • response to pH • response to zinc ion • proton transport • multicellular organism reproduction • ion transmembrane transport • regulation of ion transmembrane transport • sperm-egg recognition • cellular response to zinc ion • cellular response to pH
Sources: Amigo / QuickGO

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 12:
110.63 – 110.7 Mb

Chr 5:
122.21 – 122.24 Mb

PubMed search

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]

References

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

Li SJ, Zhao Q, Zhou Q, et al. (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. doi:10.1074/jbc.M109.040360. PMC 2852942. PMID 20147290.
Musset B, Smith SM, Rajan S, et al. (2010). "Oligomerization of the voltage-gated proton channel.". Channels (Austin) 4 (4): 260–5. PMC 3025757. PMID 20676047.
Lishko PV, Botchkina IL, Fedorenko A, Kirichok Y (2010). "Acid extrusion from human spermatozoa is mediated by flagellar voltage-gated proton channel.". Cell 140 (3): 327–37. doi:10.1016/j.cell.2009.12.053. PMID 20144758.
Kimura K, Wakamatsu A, Suzuki Y, et al. (2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
Musset B, Capasso M, Cherny VV, et al. (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. doi:10.1074/jbc.C109.082727. PMC 2820736. PMID 20037153.
Petheo GL, Orient A, Baráth M, et al. (2010). "Molecular and functional characterization of Hv1 proton channel in human granulocytes.". PLoS ONE 5 (11): e14081. doi:10.1371/journal.pone.0014081. PMC 2990768. PMID 21124855.
Sasaki M, Takagi M, Okamura Y (2006). "A voltage sensor-domain protein is a voltage-gated proton channel.". Science 312 (5773): 589–92. doi:10.1126/science.1122352. PMID 16556803.
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. doi:10.1073/pnas.0803277105. PMC 2409406. PMID 18509058.
Suzuki Y, Yamashita R, Shirota M, et al. (2004). "Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions.". Genome Res. 14 (9): 1711–8. doi:10.1101/gr.2435604. PMC 515316. PMID 15342556.
Li SJ, Zhao Q, Zhou Q, Zhai Y (2009). "Expression, purification, crystallization and preliminary crystallographic study of the carboxyl-terminal domain of the human voltage-gated proton channel Hv1.". Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 65 (Pt 3): 279–81. doi:10.1107/S1744309109003777. PMC 2650464. PMID 19255483.
Suenaga T, Arase H, Yamasaki S, et al. (2007). "Cloning of B cell-specific membrane tetraspanning molecule BTS possessing B cell proliferation-inhibitory function.". Eur. J. Immunol. 37 (11): 3197–207. doi:10.1002/eji.200737052. PMID 17948262.
Iovannisci D, Illek B, Fischer H (2010). "Function of the HVCN1 proton channel in airway epithelia and a naturally occurring mutation, M91T.". J. Gen. Physiol. 136 (1): 35–46. doi:10.1085/jgp.200910379. PMC 2894549. PMID 20548053.
Clark HF, Gurney AL, Abaya E, et al. (2003). "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. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309.
Musset B, Cherny VV, Morgan D, et al. (2008). "Detailed comparison of expressed and native voltage-gated proton channel currents.". J. Physiol. (Lond.) 586 (10): 2477–86. doi:10.1113/jphysiol.2007.149427. PMC 2464343. PMID 18356202.
Strausberg RL, Feingold EA, Grouse LH, et al. (2002). "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. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
Ramsey IS, Moran MM, Chong JA, Clapham DE (2006). "A voltage-gated proton-selective channel lacking the pore domain.". Nature 440 (7088): 1213–6. doi:10.1038/nature04700. PMID 16554753.
Sakata S, Kurokawa T, Nørholm MH, et al. (2010). "Functionality of the voltage-gated proton channel truncated in S4.". Proc. Natl. Acad. Sci. U.S.A. 107 (5): 2313–8. doi:10.1073/pnas.0911868107. PMC 2836681. PMID 20018719.

Membrane transport protein: ion channels (TC 1A)

Ca²⁺: Calcium channel

Ligand-gated	Inositol trisphosphate receptor 1 2 3 Ryanodine receptor 1 2 3

Voltage-gated	L-type/Ca_vα 1.1 1.2 1.3 1.4 N-type/Ca_vα2.2 P-type/Ca_vα 2.1 Q-type/Ca_vα2.1 R-type/Ca_vα2.3 T-type/Ca_vα 3.1 3.2 3.3 α₂δ-subunits 1 2 β-subunits β1 β2 β3 β4 γ-subunits γ1 γ2 γ3 γ4 Cation channels of sperm 1 2 3 4 Two-pore channel 1 2

Na⁺: Sodium channel

Constitutively active	Epithelial sodium channel α β γ δ

Proton-gated	Amiloride-sensitive cation channel 1 2 3 4

Voltage-gated	Na_vα 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 7A Na_vβ 1 2 3 4

K⁺: Potassium channel

Calcium-activated	BK channel α1 β1 β2 β3 β4 SK channel SK1 SK2 SK3 IK channel IK1 K_Ca 1.1 2.1 2.2 2.3 3.1 4.1 4.2 5.1

Inward-rectifier	K_ATP K_ir 1.1 2.1 2.2 2.3 2.4 2.6 GIRK/K_ir 3.1 3.2 3.3 3.4 K_ir 4.1 4.2 5.1 6.1 6.2 7.1

Tandem pore domain	K2P 1 2 3 4 5 6 7 9 10 12 13 15 16 17 18

Voltage-gated	K_vα1-6 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 2.1 2.2 3.1 3.2 3.3 3.4 4.1 4.2 4.3 5.1 6.1 6.2 6.3 6.4 K_vα7-12 7.1 7.2 7.3 7.4 7.5 8.1 8.2 9.1 9.2 9.3 10.1 10.2 11.1/hERG 11.2 11.3 12.1 12.2 12.3 K_vβ 1 2 3 KCNIP 1 2 3 4 minK/ISK minK/ISK-like MiRP 1 2 3 Shaker gene

Miscellaneous

Cl⁻: Chloride channel	Calcium-activated chloride channels Anoctamin ANO1 Bestrophin 1 2 Chloride Channel Accessory 1 2 3 4 CFTR CLCN 1 2 3 4 5 6 7 KA KB CLIC 1 2 3 4 5 6 L1 CLNS 1A 1B

H⁺: Proton channel	HVCN1

M⁺: CNG cation channel	α 1 2 3 4 β 1 2 3 HCN FC 1 2 3 4

M⁺: TRP cation channel	TRPA (1) TRPC 1 2 3 4 4AP 5 6 7 TRPM 1 2 3 4 5 6 7 8 TRPML 1 2 3 TRPN TRPP 1 2 TRPV 1 2 3 4 5 6

H₂O (+ solutes): Porin	Aquaporin 0 1 2 3 4 5 6 7 8 9 Voltage-dependent anion channel 1 2 3 General bacterial porin family

Cytoplasm: Gap junction	Connexin: A GJA1 GJA3 GJA4 GJA5 GJA8 GJA9 GJA10 B GJB1 GJB2 GJB3 GJB4 GJB5 GJB6 GJB7 C GJC1 GJC2 GJC3 D GJD2 GJD3 GJD4) Innexin

By gating mechanism

Ion channel class	Ligand-gated Light-gated Voltage-gated Stretch-activated

see also disorders

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HVCN1

As a drug target

References

Further reading