Voltage-gated proton channels: what's next?
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.
DeCoursey
Thomas E
TE
Department of Molecular Biophysics and Physiology, Rush University Medical Center, 1750 W. Harrison, Chicago, IL 60612, USA. tdecours@rush.edu
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
D007473:Ion Channels; D011522:Protons; D015032:Zinc
J Mol Biol. 1999 Feb 26;286(3):951-62
10024461
J Physiol. 1999 Apr 1;516 ( Pt 1):209-17
10066935
Neuroscience. 1999;91(4):1415-24
10391447
J Exp Med. 1999 Jul 19;190(2):183-94
10432282
J Biol Chem. 1999 Sep 10;274(37):26098-104
10473559
J Gen Physiol. 1999 Dec;114(6):771-86
10578014
J Gen Physiol. 1999 Dec;114(6):819-38
10578017
Science. 2000 Jan 7;287(5450):138-42
10615049
Biophys J. 2000 Jan;78(1):150-63
10620282
Biophys J. 2000 Apr;78(4):1825-34
10733963
Physiol Rev. 2000 Apr;80(2):555-92
10747201
Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6885-9
10823889
J Biol Chem. 2000 Oct 6;275(40):31038-50
10913133
J Virol. 2000 Sep;74(17):7755-61
10933681
Neurosci Res. 2000 Nov;38(3):265-71
11070193
J Virol. 2001 Apr;75(8):3647-56
11264354
J Gen Physiol. 2001 May;117(5):469-90
11331357
J Biol Chem. 2001 Aug 10;276(32):30277-84
11389135
J Biol Chem. 2001 Sep 28;276(39):36063-6
11477065
J Physiol. 2001 Sep 15;535(Pt 3):767-81
11559774
J Physiol. 2001 Sep 15;535(Pt 3):783-94
11559775
J Cell Physiol. 2001 Dec;189(3):306-15
11748588
Biophys J. 2002 Jan;82(1 Pt 1):182-92
11751307
J Physiol. 2002 Jan 15;538(Pt 2):371-82
11790806
Biophys J. 2002 Mar;82(3):1460-8
11867461
Am J Physiol Cell Physiol. 2002 Apr;282(4):C736-43
11880261
Nature. 2002 Mar 21;416(6878):291-7
11907569
J Neurophysiol. 2002 May;87(5):2209-24
11976362
J Physiol. 2002 May 15;541(Pt 1):139-58
12015426
Plant Cell. 1997 Nov;9(11):2077-2091
12237354
J Physiol. 2002 Nov 15;545(1):93-105
12433952
J Gen Physiol. 2002 Dec;120(6):759-65
12451045
J Gen Physiol. 2002 Dec;120(6):767-71
12451046
J Gen Physiol. 2002 Dec;120(6):773-9
12451047
J Gen Physiol. 2002 Dec;120(6):781-6
12451048
Biophys Chem. 2003 Jan 21;103(2):179-90
12568940
Physiol Rev. 2003 Apr;83(2):475-579
12663866
Nature. 2003 Apr 3;422(6931):531-4
12673252
J Gen Physiol. 2003 Jun;121(6):615-28
12771195
J Cell Sci. 2003 Aug 1;116(Pt 15):3221-6
12829741
Prog Biophys Mol Biol. 2003 Oct;83(2):69-100
12865074
FEBS Lett. 2003 Sep 18;552(1):17-22
12972146
J Biol Chem. 1992 Nov 15;267(32):22740-6
1331065
J Physiol. 1957 Jul 11;137(2):218-44
13449874
Biochem J. 1992 Feb 1;281 ( Pt 3):697-701
1371386
Adv Enzymol Relat Subj Biochem. 1963;25:1-38
14149678
J Bone Miner Res. 2003 Nov;18(11):2069-76
14606521
J Gen Physiol. 2003 Dec;122(6):713-26
14638931
Nature. 2004 Feb 5;427(6974):548-53
14765197
J Physiol. 1952 Apr;116(4):473-96
14946714
J Biol Chem. 2004 Aug 13;279(33):34553-61
15173182
J Biol Chem. 2004 Aug 27;279(35):36454-61
15210697
Blood. 2004 Nov 1;104(9):2947-53
15251984
Methods Enzymol. 1992;207:123-31
1528115
Am J Physiol Lung Cell Mol Physiol. 2005 Feb;288(2):L398-408
15516489
Science. 1992 Mar 27;255(5052):1712-5
1553560
J Leukoc Biol. 2005 May;77(5):598-625
15689384
Neuron. 2005 Feb 3;45(3):379-88
15694325
Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):4929-30
15795366
Nature. 2005 Jun 30;435(7046):1239-43
15902207
J Gen Physiol. 2005 Aug;126(2):137-50
16009728
Neuron. 2005 Jul 21;47(2):183-9
16039561
Ann N Y Acad Sci. 2005 Jun;1047:271-82
16093503
Philos Trans R Soc Lond B Biol Sci. 2005 Dec 29;360(1464):2315-25
16321802
Structure. 2005 Dec;13(12):1789-98
16338407
J Biol Chem. 2006 Mar 17;281(11):7294-301
16361256
Biochim Biophys Acta. 2006 Aug;1757(8):996-1011
16483534
J Gen Physiol. 2006 Mar;127(3):309-28
16505150
Nature. 2006 Apr 27;440(7088):1213-6
16554753
Science. 2006 Apr 28;312(5773):589-92
16556803
J Gen Physiol. 2006 Jun;127(6):659-72
16702353
Annu Rev Cell Dev Biol. 2006;22:23-52
16704338
Biochem J. 2006 Dec 15;400(3):431-8
16842239
Biochim Biophys Acta. 2006 Aug;1757(8):871-5
16962993
Pflugers Arch. 1990 Aug;416(6):758-62
1701047
J Cell Biol. 1991 Jan;112(1):125-34
1702442
Biophys J. 2007 Jan 15;92(2):641-53
17056723
Biophys J. 1991 Jul;60(1):101-9
1715764
J Physiol. 2007 Mar 1;579(Pt 2):327-44
17185330
Nature. 2007 Feb 1;445(7127):546-9
17187057
Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10816-20
1720552
Biophys J. 1991 Nov;60(5):1243-53
1722118
Proc Natl Acad Sci U S A. 2007 May 8;104(19):7904-9
17470814
J Gen Physiol. 2007 Jul;130(1):11-20
17591984
Curr Pharm Des. 2007;13(23):2400-20
17692009
Biophys J. 2007 Nov 15;93(10):3470-9
17693473
Biophys J. 2008 Jan 1;94(1):53-62
17827236
Immunol Rev. 2007 Oct;219:88-102
17850484
Nat Struct Mol Biol. 2008 Jan;15(1):106-8
18084307
J Physiol. 1949 Mar 1;108(1):37-77
18128147
Neuroscience. 2008 Feb 19;151(4):1084-98
18201832
Biochemistry. 2008 Feb 12;47(6):1778-88
18205407
Nature. 2008 Jan 31;451(7178):596-9
18235504
J Physiol. 2008 May 15;586(10):2477-86
18356202
J Biol Chem. 2008 Jun 27;283(26):18248-59
18375390
J Biol Chem. 2008 May 30;283(22):15097-103
18390554
Cell Mol Life Sci. 2008 Aug;65(16):2554-73
18463791
Neuron. 2008 May 22;58(4):546-56
18498736
Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7692-5
18509058
Semin Immunopathol. 2008 Jul;30(3):237-53
18574584
Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9111-6
18583477
Am J Hematol. 1991 Aug;37(4):263-6
1858784
J Gen Physiol. 2008 Jul;132(1):185-98
18591423
Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):11020-5
18664579
J Gen Physiol. 1943 Sep 20;27(1):37-60
19873371
J Exp Biol. 1989 Sep;145:439-54
22912992
J Exp Biol. 1989 Sep;145:455-64
22912993
J Physiol. 1986 Jul;376:477-91
2432237
J Biol Chem. 1987 Apr 5;262(10):4574-9
2435712
J Physiol. 1987 Sep;390:433-52
2450997
Pflugers Arch. 1988 Feb;411(2):204-11
2451806
Biochem J. 1988 Apr 15;251(2):563-7
2456757
Nature. 1989 Jun 22;339(6226):597-603
2543931
J Physiol. 1989 Jun;413:75-89
2557442
Proc Natl Acad Sci U S A. 1978 Jan;75(1):298-302
272644
Biochem J. 1987 Sep 1;246(2):325-9
2825632
Front Biosci. 1998 May 1;3:d477-482
28481211
Biochem J. 1988 Oct 1;255(1):285-90
2848506
J Immunol. 1986 May 1;136(9):3447-54
3007619
Biochim Biophys Acta. 1987 Jan 16;890(1):1-5
3026469
Chem Pharm Bull (Tokyo). 1988 Mar;36(3):1035-40
3409394
Rev Physiol Biochem Pharmacol. 1978;82:96-190
356157
J Biol Chem. 1986 Jul 25;261(21):9710-3
3755432
Biochim Biophys Acta. 1972 Aug 9;274(2):313-22
5049000
J Physiol. 1984 Jun;351:199-216
6086903
J Physiol. 1984 Jul;352:243-63
6086909
Ann N Y Acad Sci. 1980;339:8-20
6156618
Nature. 1984 Nov 8-14;312(5990):121-7
6209577
J Biol Chem. 1980 Mar 10;255(5):1874-8
6243652
J Clin Invest. 1980 Sep;66(3):493-503
6249851
J Clin Invest. 1981 Jul;68(1):310-3
6265500
J Membr Biol. 1983;74(1):1-14
6306243
J Clin Invest. 1984 Aug;74(2):455-9
6430961
J Biol Chem. 1984 Nov 10;259(21):13166-71
6490651
Physiol Rev. 1981 Apr;61(2):296-434
7012859
Nature. 1982 Oct 28;299(5886):826-8
7133121
Pflugers Arch. 1995 Aug;430(4):526-33
7491279
J Gen Physiol. 1995 Jul;106(1):85-111
7494140
Biophys J. 1993 Oct;65(4):1590-8
7506066
J Physiol. 1993 Oct;470:313-33
7508503
Q Rev Biophys. 1994 Feb;27(1):1-40
7520590
J Biol Chem. 1994 Nov 4;269(44):27280-5
7525551
J Membr Biol. 1994 Sep;141(3):203-23
7528804
J Gen Physiol. 1995 Jun;105(6):861-96
7561747
J Physiol. 1993 Jul;466:329-44
7692041
J Biol Chem. 1995 Mar 17;270(11):5909-16
7890722
J Gen Physiol. 1994 May;103(5):755-85
8035162
FEBS Lett. 1994 Aug 15;350(1):82-6
8062929
J Clin Invest. 1994 Apr;93(4):1770-5
8163676
Biochim Biophys Acta. 1978 Sep 22;512(2):436-51
81687
Am J Physiol. 1994 May;266(5 Pt 1):C1263-70
8203491
J Gen Physiol. 1993 Oct;102(4):729-60
8270911
Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):760-4
8421713
J Membr Biol. 1995 Sep;147(2):207-15
8568856
Neuron. 1996 Jun;16(6):1159-67
8663992
Neuron. 1996 Jun;16(6):1169-77
8663993
J Cell Biol. 1996 Jun;133(6):1391-402
8682873
J Gen Physiol. 1995 Dec;106(6):1053-68
8786350
Neuron. 1996 Feb;16(2):387-97
8789953
Biophys J. 1996 Jul;71(1):182-93
8804602
J Physiol. 1996 Jul 15;494 ( Pt 2):329-36
8841994
J Physiol. 1996 Oct 15;496 ( Pt 2):299-316
8910217
Am J Physiol. 1996 Dec;271(6 Pt 1):C1861-71
8997186
J Biol Chem. 1997 Mar 7;272(10):6354-60
9045656
J Gen Physiol. 1997 Apr;109(4):415-34
9101402
J Membr Biol. 1996 Jul;152(2):131-40
9139124
Virology. 1997 Jun 23;233(1):163-73
9201226
J Gen Physiol. 1997 Jun;109(6):731-40
9222899
Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11301-6
9326604
J Biol Chem. 1997 Oct 17;272(42):26471-8
9334224
Biophys J. 1997 Nov;73(5):2489-502
9370442
Neuron. 1997 Dec;19(6):1319-27
9427254
Nature. 1998 Apr 16;392(6677):734-7
9565037
J Gen Physiol. 1998 Oct;112(4):503-22
9758867