title: Voltage-gated proton channels: what's next?
abstract: This review is an attempt to identify and place in context some of the many questions about voltage-gated proton channels that remain unsolved. As the gene was identified only 2 years ago, the situation is very different than in fields where the gene has been known for decades. For the proton channel, most of the obvious and less obvious structure-function questions are still wide open. Remarkably, the proton channel protein strongly resembles the voltage-sensing domain of many voltage-gated ion channels, and thus offers a novel approach to study gating mechanisms. Another surprise is that the proton channel appears to function as a dimer, with two separate conduction pathways. A number of significant biological questions remain in dispute, unanswered, or in some cases, not yet asked. This latter deficit is ascribable to the intrinsic difficulty in evaluating the importance of one component in a complex system, and in addition, to the lack, until recently, of a means of performing an unambiguous lesion experiment, that is, of selectively eliminating the molecule in question. We still lack a potent, selective pharmacological inhibitor, but the identification of the gene has allowed the development of powerful new tools including proton channel antibodies, siRNA and knockout mice.
authors.affiliation: Department of Molecular Biophysics and Physiology, Rush University Medical Center, 1750 W. Harrison, Chicago, IL 60612, USA. tdecours@rush.edu
authors.forename: Thomas E
authors.initials: TE
authors.lastname: DeCoursey
mesh_terms: D000818:Animals; D001665:Binding Sites; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D010766:Phosphorylation; D011522:Protons; D015032:Zinc / Q000378:metabolism
chemical_list: D007473:Ion Channels; D011522:Protons; D015032:Zinc
references.citation: J Mol Biol. 1999 Feb 26;286(3):951-62
references.pmid: 10024461
references.citation: J Physiol. 1999 Apr 1;516 ( Pt 1):209-17
references.pmid: 10066935
references.citation: Neuroscience. 1999;91(4):1415-24
references.pmid: 10391447
references.citation: J Exp Med. 1999 Jul 19;190(2):183-94
references.pmid: 10432282
references.citation: J Biol Chem. 1999 Sep 10;274(37):26098-104
references.pmid: 10473559
references.citation: J Gen Physiol. 1999 Dec;114(6):771-86
references.pmid: 10578014
references.citation: J Gen Physiol. 1999 Dec;114(6):819-38
references.pmid: 10578017
references.citation: Science. 2000 Jan 7;287(5450):138-42
references.pmid: 10615049
references.citation: Biophys J. 2000 Jan;78(1):150-63
references.pmid: 10620282
references.citation: Biophys J. 2000 Apr;78(4):1825-34
references.pmid: 10733963
references.citation: Physiol Rev. 2000 Apr;80(2):555-92
references.pmid: 10747201
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6885-9
references.pmid: 10823889
references.citation: J Biol Chem. 2000 Oct 6;275(40):31038-50
references.pmid: 10913133
references.citation: J Virol. 2000 Sep;74(17):7755-61
references.pmid: 10933681
references.citation: Neurosci Res. 2000 Nov;38(3):265-71
references.pmid: 11070193
references.citation: J Virol. 2001 Apr;75(8):3647-56
references.pmid: 11264354
references.citation: J Gen Physiol. 2001 May;117(5):469-90
references.pmid: 11331357
references.citation: J Biol Chem. 2001 Aug 10;276(32):30277-84
references.pmid: 11389135
references.citation: J Biol Chem. 2001 Sep 28;276(39):36063-6
references.pmid: 11477065
references.citation: J Physiol. 2001 Sep 15;535(Pt 3):767-81
references.pmid: 11559774
references.citation: J Physiol. 2001 Sep 15;535(Pt 3):783-94
references.pmid: 11559775
references.citation: J Cell Physiol. 2001 Dec;189(3):306-15
references.pmid: 11748588
references.citation: Biophys J. 2002 Jan;82(1 Pt 1):182-92
references.pmid: 11751307
references.citation: J Physiol. 2002 Jan 15;538(Pt 2):371-82
references.pmid: 11790806
references.citation: Biophys J. 2002 Mar;82(3):1460-8
references.pmid: 11867461
references.citation: Am J Physiol Cell Physiol. 2002 Apr;282(4):C736-43
references.pmid: 11880261
references.citation: Nature. 2002 Mar 21;416(6878):291-7
references.pmid: 11907569
references.citation: J Neurophysiol. 2002 May;87(5):2209-24
references.pmid: 11976362
references.citation: J Physiol. 2002 May 15;541(Pt 1):139-58
references.pmid: 12015426
references.citation: Plant Cell. 1997 Nov;9(11):2077-2091
references.pmid: 12237354
references.citation: J Physiol. 2002 Nov 15;545(1):93-105
references.pmid: 12433952
references.citation: J Gen Physiol. 2002 Dec;120(6):759-65
references.pmid: 12451045
references.citation: J Gen Physiol. 2002 Dec;120(6):767-71
references.pmid: 12451046
references.citation: J Gen Physiol. 2002 Dec;120(6):773-9
references.pmid: 12451047
references.citation: J Gen Physiol. 2002 Dec;120(6):781-6
references.pmid: 12451048
references.citation: Biophys Chem. 2003 Jan 21;103(2):179-90
references.pmid: 12568940
references.citation: Physiol Rev. 2003 Apr;83(2):475-579
references.pmid: 12663866
references.citation: Nature. 2003 Apr 3;422(6931):531-4
references.pmid: 12673252
references.citation: J Gen Physiol. 2003 Jun;121(6):615-28
references.pmid: 12771195
references.citation: J Cell Sci. 2003 Aug 1;116(Pt 15):3221-6
references.pmid: 12829741
references.citation: Prog Biophys Mol Biol. 2003 Oct;83(2):69-100
references.pmid: 12865074
references.citation: FEBS Lett. 2003 Sep 18;552(1):17-22
references.pmid: 12972146
references.citation: J Biol Chem. 1992 Nov 15;267(32):22740-6
references.pmid: 1331065
references.citation: J Physiol. 1957 Jul 11;137(2):218-44
references.pmid: 13449874
references.citation: Biochem J. 1992 Feb 1;281 ( Pt 3):697-701
references.pmid: 1371386
references.citation: Adv Enzymol Relat Subj Biochem. 1963;25:1-38
references.pmid: 14149678
references.citation: J Bone Miner Res. 2003 Nov;18(11):2069-76
references.pmid: 14606521
references.citation: J Gen Physiol. 2003 Dec;122(6):713-26
references.pmid: 14638931
references.citation: Nature. 2004 Feb 5;427(6974):548-53
references.pmid: 14765197
references.citation: J Physiol. 1952 Apr;116(4):473-96
references.pmid: 14946714
references.citation: J Biol Chem. 2004 Aug 13;279(33):34553-61
references.pmid: 15173182
references.citation: J Biol Chem. 2004 Aug 27;279(35):36454-61
references.pmid: 15210697
references.citation: Blood. 2004 Nov 1;104(9):2947-53
references.pmid: 15251984
references.citation: Methods Enzymol. 1992;207:123-31
references.pmid: 1528115
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Feb;288(2):L398-408
references.pmid: 15516489
references.citation: Science. 1992 Mar 27;255(5052):1712-5
references.pmid: 1553560
references.citation: J Leukoc Biol. 2005 May;77(5):598-625
references.pmid: 15689384
references.citation: Neuron. 2005 Feb 3;45(3):379-88
references.pmid: 15694325
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):4929-30
references.pmid: 15795366
references.citation: Nature. 2005 Jun 30;435(7046):1239-43
references.pmid: 15902207
references.citation: J Gen Physiol. 2005 Aug;126(2):137-50
references.pmid: 16009728
references.citation: Neuron. 2005 Jul 21;47(2):183-9
references.pmid: 16039561
references.citation: Ann N Y Acad Sci. 2005 Jun;1047:271-82
references.pmid: 16093503
references.citation: Philos Trans R Soc Lond B Biol Sci. 2005 Dec 29;360(1464):2315-25
references.pmid: 16321802
references.citation: Structure. 2005 Dec;13(12):1789-98
references.pmid: 16338407
references.citation: J Biol Chem. 2006 Mar 17;281(11):7294-301
references.pmid: 16361256
references.citation: Biochim Biophys Acta. 2006 Aug;1757(8):996-1011
references.pmid: 16483534
references.citation: J Gen Physiol. 2006 Mar;127(3):309-28
references.pmid: 16505150
references.citation: Nature. 2006 Apr 27;440(7088):1213-6
references.pmid: 16554753
references.citation: Science. 2006 Apr 28;312(5773):589-92
references.pmid: 16556803
references.citation: J Gen Physiol. 2006 Jun;127(6):659-72
references.pmid: 16702353
references.citation: Annu Rev Cell Dev Biol. 2006;22:23-52
references.pmid: 16704338
references.citation: Biochem J. 2006 Dec 15;400(3):431-8
references.pmid: 16842239
references.citation: Biochim Biophys Acta. 2006 Aug;1757(8):871-5
references.pmid: 16962993
references.citation: Pflugers Arch. 1990 Aug;416(6):758-62
references.pmid: 1701047
references.citation: J Cell Biol. 1991 Jan;112(1):125-34
references.pmid: 1702442
references.citation: Biophys J. 2007 Jan 15;92(2):641-53
references.pmid: 17056723
references.citation: Biophys J. 1991 Jul;60(1):101-9
references.pmid: 1715764
references.citation: J Physiol. 2007 Mar 1;579(Pt 2):327-44
references.pmid: 17185330
references.citation: Nature. 2007 Feb 1;445(7127):546-9
references.pmid: 17187057
references.citation: Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10816-20
references.pmid: 1720552
references.citation: Biophys J. 1991 Nov;60(5):1243-53
references.pmid: 1722118
references.citation: Proc Natl Acad Sci U S A. 2007 May 8;104(19):7904-9
references.pmid: 17470814
references.citation: J Gen Physiol. 2007 Jul;130(1):11-20
references.pmid: 17591984
references.citation: Curr Pharm Des. 2007;13(23):2400-20
references.pmid: 17692009
references.citation: Biophys J. 2007 Nov 15;93(10):3470-9
references.pmid: 17693473
references.citation: Biophys J. 2008 Jan 1;94(1):53-62
references.pmid: 17827236
references.citation: Immunol Rev. 2007 Oct;219:88-102
references.pmid: 17850484
references.citation: Nat Struct Mol Biol. 2008 Jan;15(1):106-8
references.pmid: 18084307
references.citation: J Physiol. 1949 Mar 1;108(1):37-77
references.pmid: 18128147
references.citation: Neuroscience. 2008 Feb 19;151(4):1084-98
references.pmid: 18201832
references.citation: Biochemistry. 2008 Feb 12;47(6):1778-88
references.pmid: 18205407
references.citation: Nature. 2008 Jan 31;451(7178):596-9
references.pmid: 18235504
references.citation: J Physiol. 2008 May 15;586(10):2477-86
references.pmid: 18356202
references.citation: J Biol Chem. 2008 Jun 27;283(26):18248-59
references.pmid: 18375390
references.citation: J Biol Chem. 2008 May 30;283(22):15097-103
references.pmid: 18390554
references.citation: Cell Mol Life Sci. 2008 Aug;65(16):2554-73
references.pmid: 18463791
references.citation: Neuron. 2008 May 22;58(4):546-56
references.pmid: 18498736
references.citation: Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7692-5
references.pmid: 18509058
references.citation: Semin Immunopathol. 2008 Jul;30(3):237-53
references.pmid: 18574584
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9111-6
references.pmid: 18583477
references.citation: Am J Hematol. 1991 Aug;37(4):263-6
references.pmid: 1858784
references.citation: J Gen Physiol. 2008 Jul;132(1):185-98
references.pmid: 18591423
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):11020-5
references.pmid: 18664579
references.citation: J Gen Physiol. 1943 Sep 20;27(1):37-60
references.pmid: 19873371
references.citation: J Exp Biol. 1989 Sep;145:439-54
references.pmid: 22912992
references.citation: J Exp Biol. 1989 Sep;145:455-64
references.pmid: 22912993
references.citation: J Physiol. 1986 Jul;376:477-91
references.pmid: 2432237
references.citation: J Biol Chem. 1987 Apr 5;262(10):4574-9
references.pmid: 2435712
references.citation: J Physiol. 1987 Sep;390:433-52
references.pmid: 2450997
references.citation: Pflugers Arch. 1988 Feb;411(2):204-11
references.pmid: 2451806
references.citation: Biochem J. 1988 Apr 15;251(2):563-7
references.pmid: 2456757
references.citation: Nature. 1989 Jun 22;339(6226):597-603
references.pmid: 2543931
references.citation: J Physiol. 1989 Jun;413:75-89
references.pmid: 2557442
references.citation: Proc Natl Acad Sci U S A. 1978 Jan;75(1):298-302
references.pmid: 272644
references.citation: Biochem J. 1987 Sep 1;246(2):325-9
references.pmid: 2825632
references.citation: Front Biosci. 1998 May 1;3:d477-482
references.pmid: 28481211
references.citation: Biochem J. 1988 Oct 1;255(1):285-90
references.pmid: 2848506
references.citation: J Immunol. 1986 May 1;136(9):3447-54
references.pmid: 3007619
references.citation: Biochim Biophys Acta. 1987 Jan 16;890(1):1-5
references.pmid: 3026469
references.citation: Chem Pharm Bull (Tokyo). 1988 Mar;36(3):1035-40
references.pmid: 3409394
references.citation: Rev Physiol Biochem Pharmacol. 1978;82:96-190
references.pmid: 356157
references.citation: J Biol Chem. 1986 Jul 25;261(21):9710-3
references.pmid: 3755432
references.citation: Biochim Biophys Acta. 1972 Aug 9;274(2):313-22
references.pmid: 5049000
references.citation: J Physiol. 1984 Jun;351:199-216
references.pmid: 6086903
references.citation: J Physiol. 1984 Jul;352:243-63
references.pmid: 6086909
references.citation: Ann N Y Acad Sci. 1980;339:8-20
references.pmid: 6156618
references.citation: Nature. 1984 Nov 8-14;312(5990):121-7
references.pmid: 6209577
references.citation: J Biol Chem. 1980 Mar 10;255(5):1874-8
references.pmid: 6243652
references.citation: J Clin Invest. 1980 Sep;66(3):493-503
references.pmid: 6249851
references.citation: J Clin Invest. 1981 Jul;68(1):310-3
references.pmid: 6265500
references.citation: J Membr Biol. 1983;74(1):1-14
references.pmid: 6306243
references.citation: J Clin Invest. 1984 Aug;74(2):455-9
references.pmid: 6430961
references.citation: J Biol Chem. 1984 Nov 10;259(21):13166-71
references.pmid: 6490651
references.citation: Physiol Rev. 1981 Apr;61(2):296-434
references.pmid: 7012859
references.citation: Nature. 1982 Oct 28;299(5886):826-8
references.pmid: 7133121
references.citation: Pflugers Arch. 1995 Aug;430(4):526-33
references.pmid: 7491279
references.citation: J Gen Physiol. 1995 Jul;106(1):85-111
references.pmid: 7494140
references.citation: Biophys J. 1993 Oct;65(4):1590-8
references.pmid: 7506066
references.citation: J Physiol. 1993 Oct;470:313-33
references.pmid: 7508503
references.citation: Q Rev Biophys. 1994 Feb;27(1):1-40
references.pmid: 7520590
references.citation: J Biol Chem. 1994 Nov 4;269(44):27280-5
references.pmid: 7525551
references.citation: J Membr Biol. 1994 Sep;141(3):203-23
references.pmid: 7528804
references.citation: J Gen Physiol. 1995 Jun;105(6):861-96
references.pmid: 7561747
references.citation: J Physiol. 1993 Jul;466:329-44
references.pmid: 7692041
references.citation: J Biol Chem. 1995 Mar 17;270(11):5909-16
references.pmid: 7890722
references.citation: J Gen Physiol. 1994 May;103(5):755-85
references.pmid: 8035162
references.citation: FEBS Lett. 1994 Aug 15;350(1):82-6
references.pmid: 8062929
references.citation: J Clin Invest. 1994 Apr;93(4):1770-5
references.pmid: 8163676
references.citation: Biochim Biophys Acta. 1978 Sep 22;512(2):436-51
references.pmid: 81687
references.citation: Am J Physiol. 1994 May;266(5 Pt 1):C1263-70
references.pmid: 8203491
references.citation: J Gen Physiol. 1993 Oct;102(4):729-60
references.pmid: 8270911
references.citation: Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):760-4
references.pmid: 8421713
references.citation: J Membr Biol. 1995 Sep;147(2):207-15
references.pmid: 8568856
references.citation: Neuron. 1996 Jun;16(6):1159-67
references.pmid: 8663992
references.citation: Neuron. 1996 Jun;16(6):1169-77
references.pmid: 8663993
references.citation: J Cell Biol. 1996 Jun;133(6):1391-402
references.pmid: 8682873
references.citation: J Gen Physiol. 1995 Dec;106(6):1053-68
references.pmid: 8786350
references.citation: Neuron. 1996 Feb;16(2):387-97
references.pmid: 8789953
references.citation: Biophys J. 1996 Jul;71(1):182-93
references.pmid: 8804602
references.citation: J Physiol. 1996 Jul 15;494 ( Pt 2):329-36
references.pmid: 8841994
references.citation: J Physiol. 1996 Oct 15;496 ( Pt 2):299-316
references.pmid: 8910217
references.citation: Am J Physiol. 1996 Dec;271(6 Pt 1):C1861-71
references.pmid: 8997186
references.citation: J Biol Chem. 1997 Mar 7;272(10):6354-60
references.pmid: 9045656
references.citation: J Gen Physiol. 1997 Apr;109(4):415-34
references.pmid: 9101402
references.citation: J Membr Biol. 1996 Jul;152(2):131-40
references.pmid: 9139124
references.citation: Virology. 1997 Jun 23;233(1):163-73
references.pmid: 9201226
references.citation: J Gen Physiol. 1997 Jun;109(6):731-40
references.pmid: 9222899
references.citation: Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11301-6
references.pmid: 9326604
references.citation: J Biol Chem. 1997 Oct 17;272(42):26471-8
references.pmid: 9334224
references.citation: Biophys J. 1997 Nov;73(5):2489-502
references.pmid: 9370442
references.citation: Neuron. 1997 Dec;19(6):1319-27
references.pmid: 9427254
references.citation: Nature. 1998 Apr 16;392(6677):734-7
references.pmid: 9565037
references.citation: J Gen Physiol. 1998 Oct;112(4):503-22
references.pmid: 9758867