title: Molecular mechanism of voltage sensing in voltage-gated proton channels.
abstract: Voltage-gated proton (Hv) channels play an essential role in phagocytic cells by generating a hyperpolarizing proton current that electrically compensates for the depolarizing current generated by the NADPH oxidase during the respiratory burst, thereby ensuring a sustained production of reactive oxygen species by the NADPH oxidase in phagocytes to neutralize engulfed bacteria. Despite the importance of the voltage-dependent Hv current, it is at present unclear which residues in Hv channels are responsible for the voltage activation. Here we show that individual neutralizations of three charged residues in the fourth transmembrane domain, S4, all reduce the voltage dependence of activation. In addition, we show that the middle S4 charged residue moves from a position accessible from the cytosolic solution to a position accessible from the extracellular solution, suggesting that this residue moves across most of the membrane electric field during voltage activation of Hv channels. Our results show for the first time that the charge movement of these three S4 charges accounts for almost all of the measured gating charge in Hv channels.
authors: Department of Physiology and Biophysics, University of Miami, Miami, FL 33136, USA. carlos.gonzalezl@uv
authors: Carlos
authors: C
authors: Gonzalez
authors: Santiago
authors: S
authors: Rebolledo
authors: Marta E
authors: ME
authors: Perez
authors: H Peter
authors: HP
authors: Larsson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism / Q000502:physiology; D004594:Electrophysiology / Q000379:methods; D015640:Ion Channel Gating / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology*; D008969:Molecular Sequence Data; D009865:Oocytes / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D017494:Proton Pumps / Q000378:metabolism*; D011522:Protons; D014982:Xenopus laevis
chemical_list: D017494:Proton Pumps; D011522:Protons
references: Physiol Rev. 2003 Apr;83(2):475-579
references: 12663866
references: Neuron. 2007 Oct 4;56(1):124-40
references: 17920020
references: J Gen Physiol. 1995 Dec;106(6):1053-68
references: 8786350
references: Science. 1996 Jan 12;271(5246):213-6
references: 8539623
references: Neuron. 2008 May 22;58(4):546-56
references: 18498736
references: Proc Natl Acad Sci U S A. 2009 May 5;106(18):7642-7
references: 19372380
references: Cell. 2010 Feb 5;140(3):327-37
references: 20144758
references: J Gen Physiol. 1997 Jan;109(1):27-39
references: 8997663
references: Neuron. 1998 Jun;20(6):1283-94
references: 9655514
references: Nature. 2007 Nov 15;450(7168):376-82
references: 18004376
references: Biophys J. 2010 May 19;98(10):2189-98
references: 20483327
references: Nature. 2006 Apr 27;440(7088):1213-6
references: 16554753
references: Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2313-8
references: 20018719
references: Neuron. 1996 Jan;16(1):113-22
references: 8562074
references: Neuron. 1996 Feb;16(2):387-97
references: 8789953
references: Science. 2005 Aug 5;309(5736):897-903
references: 16002581
references: Annu Rev Cell Dev Biol. 2006;22:23-52
references: 16704338
references: Neuron. 1996 Jun;16(6):1169-77
references: 8663993
references: Biochem Biophys Res Commun. 2009 May 1;382(2):274-9
references: 19285483
references: Neuron. 1996 Jun;16(6):1159-67
references: 8663992
references: Rev Physiol Biochem Pharmacol. 1978;82:96-190
references: 356157
references: Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7692-5
references: 18509058
references: J Gen Physiol. 1981 Jan;77(1):1-22
references: 6162910
references: Nat Struct Mol Biol. 2010 Jan;17(1):51-6
references: 20023639
references: J Gen Physiol. 2007 Jul;130(1):71-81
references: 17591986
references: J Gen Physiol. 2010 Jul;136(1):35-46
references: 20548053
references: Nat Struct Mol Biol. 2010 Jan;17(1):44-50
references: 20023640
references: Science. 2012 Apr 13;336(6078):229-33
references: 22499946
references: J Gen Physiol. 1985 Jan;85(1):65-82
references: 2578549
references: Nature. 2003 May 1;423(6935):33-41
references: 12721618
references: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9111-6
references: 18583477
references: J Gen Physiol. 2003 Jun;121(6):615-28
references: 12771195
references: J Gen Physiol. 1994 Feb;103(2):279-319
references: 8189207
references: Science. 2006 Apr 28;312(5773):589-92
references: 16556803