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Proc Natl Acad Sci U S A
2012 Nov 20;10947:19250-5. doi: 10.1073/pnas.1217990109.
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Gating pore currents and the resting state of Nav1.4 voltage sensor domains.
Gosselin-Badaroudine P, Delemotte L, Moreau A, Klein ML, Chahine M.
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Mammalian voltage-gated sodium channels are composed of four homologous voltage sensor domains (VSDs; DI, DII, DIII, and DIV) in which their S4 segments contain a variable number of positively charged residues. We used single histidine (H) substitutions of these charged residues in the Na(v)1.4 channel to probe the positions of the S4 segments at hyperpolarized potentials. The substitutions led to the formation of gating pores that were detected as proton leak currents through the VSDs. The leak currents indicated that the mutated residues are accessible from both sides of the membrane. Leak currents of different magnitudes appeared in the DI/R1H, DII/R1H, and DIII/R2H mutants, suggesting that the resting state position of S4 varies depending on the domain. Here, DI/R1H indicates the first arginine R1, in domain DI, has been mutated to histidine. The single R1H, R2H, and R3H mutations in DIV did not produce appreciable proton currents, indicating that the VSDs had different topologies. A structural model of the resting states of the four VSDs of Na(v)1.4 relaxed in their membrane/solution environment using molecular dynamics simulations is proposed based on the recent Na(v)Ab sodium channel X-ray structure. The model shows that the hydrophobic septa that isolate the intracellular and the extracellular media within the DI, DII, and DIII VSDs are ∼2 Å long, similar to those of K(v) channels. However, the septum of DIV is longer, which prevents water molecules from hydrating the center of the VSD, thus breaking the proton conduction pathway. This structural model rationalizes the activation sequence of the different VSDs of the Na(v)1.4 channel.
Altschul,
Basic local alignment search tool.
1990, Pubmed
Altschul,
Basic local alignment search tool.
1990,
Pubmed Bezanilla,
The voltage-sensor structure in a voltage-gated channel.
2005,
Pubmed Capes,
Gating transitions in the selectivity filter region of a sodium channel are coupled to the domain IV voltage sensor.
2012,
Pubmed Chahine,
Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation.
1994,
Pubmed Chanda,
Tracking voltage-dependent conformational changes in skeletal muscle sodium channel during activation.
2002,
Pubmed
,
Xenbase Chen,
Origins of proton transport behavior from selectivity domain mutations of the aquaporin-1 channel.
2006,
Pubmed Delemotte,
Effect of sensor domain mutations on the properties of voltage-gated ion channels: molecular dynamics studies of the potassium channel Kv1.2.
2010,
Pubmed Delemotte,
Intermediate states of the Kv1.2 voltage sensor from atomistic molecular dynamics simulations.
2011,
Pubmed Francis,
Leaky sodium channels from voltage sensor mutations in periodic paralysis, but not paramyotonia.
2011,
Pubmed Freites,
A voltage-sensor water pore.
2006,
Pubmed Geissler,
Autoionization in liquid water.
2001,
Pubmed Gosselin-Badaroudine,
A proton leak current through the cardiac sodium channel is linked to mixed arrhythmia and the dilated cardiomyopathy phenotype.
2012,
Pubmed
,
Xenbase Hassanali,
On the recombination of hydronium and hydroxide ions in water.
2011,
Pubmed Jensen,
Mechanism of voltage gating in potassium channels.
2012,
Pubmed Jogini,
Dynamics of the Kv1.2 voltage-gated K+ channel in a membrane environment.
2007,
Pubmed Jurkat-Rott,
Pathophysiological role of omega pore current in channelopathies.
2012,
Pubmed Khalili-Araghi,
Molecular dynamics investigation of the ω-current in the Kv1.2 voltage sensor domains.
2012,
Pubmed Krepkiy,
Structure and hydration of membranes embedded with voltage-sensing domains.
2009,
Pubmed MacCallum,
Partitioning of amino acid side chains into lipid bilayers: results from computer simulations and comparison to experiment.
2007,
Pubmed Payandeh,
The crystal structure of a voltage-gated sodium channel.
2011,
Pubmed Payandeh,
Crystal structure of a voltage-gated sodium channel in two potentially inactivated states.
2012,
Pubmed Pless,
Contributions of counter-charge in a potassium channel voltage-sensor domain.
2011,
Pubmed
,
Xenbase Pomès,
Molecular mechanism of H+ conduction in the single-file water chain of the gramicidin channel.
2002,
Pubmed Sokolov,
Gating pore current in an inherited ion channelopathy.
2007,
Pubmed
,
Xenbase Sokolov,
Depolarization-activated gating pore current conducted by mutant sodium channels in potassium-sensitive normokalemic periodic paralysis.
2008,
Pubmed
,
Xenbase Sokolov,
Ion permeation through a voltage- sensitive gating pore in brain sodium channels having voltage sensor mutations.
2005,
Pubmed
,
Xenbase Starace,
Histidine scanning mutagenesis of basic residues of the S4 segment of the shaker k+ channel.
2001,
Pubmed
,
Xenbase Starace,
A proton pore in a potassium channel voltage sensor reveals a focused electric field.
2004,
Pubmed Struyk,
A Na+ channel mutation linked to hypokalemic periodic paralysis exposes a proton-selective gating pore.
2007,
Pubmed
,
Xenbase Stühmer,
Structural parts involved in activation and inactivation of the sodium channel.
1989,
Pubmed
,
Xenbase Tao,
A gating charge transfer center in voltage sensors.
2010,
Pubmed
,
Xenbase Tikhonov,
Architecture and pore block of eukaryotic voltage-gated sodium channels in view of NavAb bacterial sodium channel structure.
2012,
Pubmed Tombola,
Voltage-sensing arginines in a potassium channel permeate and occlude cation-selective pores.
2005,
Pubmed
,
Xenbase Treptow,
Environment of the gating charges in the Kv1.2 Shaker potassium channel.
2006,
Pubmed Yang,
Molecular basis of charge movement in voltage-gated sodium channels.
1996,
Pubmed Yarov-Yarovoy,
Structural basis for gating charge movement in the voltage sensor of a sodium channel.
2012,
Pubmed Zhang,
Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel.
2012,
Pubmed
