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J Physiol
2006 Nov 01;576Pt 3:739-54. doi: 10.1113/jphysiol.2006.115105.
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A conserved ring of charge in mammalian Na+ channels: a molecular regulator of the outer pore conformation during slow inactivation.
Xiong W, Farukhi YZ, Tian Y, Disilvestre D, Li RA, Tomaselli GF.
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The molecular mechanisms underlying slow inactivation in sodium channels are elusive. Our results suggest that EEDD, a highly conserved ring of charge in the external vestibule of mammalian voltage-gated sodium channels, undermines slow inactivation. By employing site-directed mutagenesis, we found that charge alterations in this asymmetric yet strong local electrostatic field of the EEDD ring significantly altered the kinetics of slow inactivation gating. Using a non-linear Poisson-Boltzmann equation, quantitative computations of the electrostatic field in a sodium channel structural model suggested a significant electrostatic repulsion between residues E403 and E758 at close proximity. Interestingly, when this electrostatic interaction was eliminated by the double mutation E403C + E758C, the kinetics of recovery from slow inactivation of the double-mutant channel was retarded by 2500% compared to control. These data suggest that the EEDD ring, located within the asymmetric electric field, is a molecular motif that critically modulates slow inactivation in sodium channels.
Adelman,
The effects of external potassium and long duration voltage conditioning on the amplitude of sodium currents in the giant axon of the squid, Loligo pealei.
1969, Pubmed
Adelman,
The effects of external potassium and long duration voltage conditioning on the amplitude of sodium currents in the giant axon of the squid, Loligo pealei.
1969,
Pubmed Alekov,
Enhanced inactivation and acceleration of activation of the sodium channel associated with epilepsy in man.
2001,
Pubmed Balser,
External pore residue mediates slow inactivation in mu 1 rat skeletal muscle sodium channels.
1996,
Pubmed
,
Xenbase Bendahhou,
Activation and inactivation of the voltage-gated sodium channel: role of segment S5 revealed by a novel hyperkalaemic periodic paralysis mutation.
1999,
Pubmed Bendahhou,
Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5.
2002,
Pubmed Bénitah,
Molecular motions within the pore of voltage-dependent sodium channels.
1997,
Pubmed
,
Xenbase Boland,
Cysteines in the Shaker K+ channel are not essential for channel activity or zinc modulation.
1994,
Pubmed
,
Xenbase Cha,
Voltage sensors in domains III and IV, but not I and II, are immobilized by Na+ channel fast inactivation.
1999,
Pubmed
,
Xenbase Cha,
Characterizing voltage-dependent conformational changes in the Shaker K+ channel with fluorescence.
1997,
Pubmed
,
Xenbase Chang,
Predominant interactions between mu-conotoxin Arg-13 and the skeletal muscle Na+ channel localized by mutant cycle analysis.
1998,
Pubmed
,
Xenbase Choi,
Tetraethylammonium blockade distinguishes two inactivation mechanisms in voltage-activated K+ channels.
1991,
Pubmed Cordero-Morales,
Molecular determinants of gating at the potassium-channel selectivity filter.
2006,
Pubmed Cummins,
Impaired slow inactivation in mutant sodium channels.
1996,
Pubmed De Biasi,
Inactivation determined by a single site in K+ pores.
1993,
Pubmed Do,
Subthreshold sodium currents and pacemaking of subthalamic neurons: modulation by slow inactivation.
2003,
Pubmed Dudley,
A mu-conotoxin-insensitive Na+ channel mutant: possible localization of a binding site at the outer vestibule.
1995,
Pubmed Elinder,
S4 charges move close to residues in the pore domain during activation in a K channel.
2001,
Pubmed
,
Xenbase Featherstone,
Interaction between fast and slow inactivation in Skm1 sodium channels.
1996,
Pubmed
,
Xenbase Fukuda,
Compound-specific Na+ channel pore conformational changes induced by local anaesthetics.
2005,
Pubmed Gilson,
Calculation of electrostatic potentials in an enzyme active site.
,
Pubmed Green,
Batrachotoxin-modified sodium channels in planar lipid bilayers. Ion permeation and block.
1987,
Pubmed Groenewegen,
A novel LQT3 mutation implicates the human cardiac sodium channel domain IVS6 in inactivation kinetics.
2003,
Pubmed
,
Xenbase Harris,
A permanent ion binding site located between two gates of the Shaker K+ channel.
1998,
Pubmed
,
Xenbase Hayward,
Slow inactivation differs among mutant Na channels associated with myotonia and periodic paralysis.
1997,
Pubmed Hilber,
The selectivity filter of the voltage-gated sodium channel is involved in channel activation.
2001,
Pubmed
,
Xenbase Hilber,
Interaction between fast and ultra-slow inactivation in the voltage-gated sodium channel. Does the inactivation gate stabilize the channel structure?
2002,
Pubmed
,
Xenbase Hirschberg,
Transfer of twelve charges is needed to open skeletal muscle Na+ channels.
1995,
Pubmed
,
Xenbase Hoshi,
Two types of inactivation in Shaker K+ channels: effects of alterations in the carboxy-terminal region.
1991,
Pubmed
,
Xenbase Hoshi,
Biophysical and molecular mechanisms of Shaker potassium channel inactivation.
1990,
Pubmed
,
Xenbase Hui,
Conotoxins as sensors of local pH and electrostatic potential in the outer vestibule of the sodium channel.
2003,
Pubmed Isom,
Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel.
1992,
Pubmed
,
Xenbase Kambouris,
Mechanistic link between lidocaine block and inactivation probed by outer pore mutations in the rat micro1 skeletal muscle sodium channel.
1998,
Pubmed
,
Xenbase Kass,
Sodium channel inactivation goes with the flow.
2004,
Pubmed Khan,
Role of outer ring carboxylates of the rat skeletal muscle sodium channel pore in proton block.
2002,
Pubmed
,
Xenbase Kiss,
Modulation of C-type inactivation by K+ at the potassium channel selectivity filter.
1998,
Pubmed Kontis,
Sodium channel inactivation is altered by substitution of voltage sensor positive charges.
1997,
Pubmed
,
Xenbase Lipkind,
KcsA crystal structure as framework for a molecular model of the Na(+) channel pore.
2000,
Pubmed Liu,
Dynamic rearrangement of the outer mouth of a K+ channel during gating.
1996,
Pubmed Loots,
Protein rearrangements underlying slow inactivation of the Shaker K+ channel.
1998,
Pubmed Loots,
Molecular coupling of S4 to a K(+) channel's slow inactivation gate.
2000,
Pubmed Mitrovic,
Role of domain 4 in sodium channel slow inactivation.
2000,
Pubmed Olcese,
Correlation between charge movement and ionic current during slow inactivation in Shaker K+ channels.
1997,
Pubmed
,
Xenbase Ong,
A structural rearrangement in the sodium channel pore linked to slow inactivation and use dependence.
2000,
Pubmed O'Reilly,
Comparison of slow inactivation in human heart and rat skeletal muscle Na+ channel chimaeras.
1999,
Pubmed O'Reilly,
Residue-specific effects on slow inactivation at V787 in D2-S6 of Na(v)1.4 sodium channels.
2001,
Pubmed Pathak,
The cooperative voltage sensor motion that gates a potassium channel.
2005,
Pubmed
,
Xenbase Patton,
Amino acid residues required for fast Na(+)-channel inactivation: charge neutralizations and deletions in the III-IV linker.
1992,
Pubmed Pavlov,
The pore, not cytoplasmic domains, underlies inactivation in a prokaryotic sodium channel.
2005,
Pubmed Richmond,
Slow inactivation in human cardiac sodium channels.
1998,
Pubmed
,
Xenbase Ruff,
Comparison between slow sodium channel inactivation in rat slow- and fast-twitch muscle.
1987,
Pubmed Simoncini,
Slow sodium channel inactivation in rat fast-twitch muscle.
1987,
Pubmed Spampanato,
Increased neuronal firing in computer simulations of sodium channel mutations that cause generalized epilepsy with febrile seizures plus.
2004,
Pubmed
,
Xenbase Struyk,
Slow inactivation does not block the aqueous accessibility to the outer pore of voltage-gated Na channels.
2002,
Pubmed
,
Xenbase Stühmer,
Structural parts involved in activation and inactivation of the sodium channel.
1989,
Pubmed
,
Xenbase Todt,
Ultra-slow inactivation in mu1 Na+ channels is produced by a structural rearrangement of the outer vestibule.
1999,
Pubmed
,
Xenbase Tomaselli,
A mutation in the pore of the sodium channel alters gating.
1995,
Pubmed
,
Xenbase Townsend,
Effect of alkali metal cations on slow inactivation of cardiac Na+ channels.
1997,
Pubmed
,
Xenbase Trimmer,
Primary structure and functional expression of a mammalian skeletal muscle sodium channel.
1989,
Pubmed
,
Xenbase Tsang,
A multifunctional aromatic residue in the external pore vestibule of Na+ channels contributes to the local anesthetic receptor.
2005,
Pubmed
,
Xenbase Vassilev,
Inhibition of inactivation of single sodium channels by a site-directed antibody.
1989,
Pubmed Veldkamp,
Two distinct congenital arrhythmias evoked by a multidysfunctional Na(+) channel.
2000,
Pubmed Vilin,
Structural determinants of slow inactivation in human cardiac and skeletal muscle sodium channels.
1999,
Pubmed
,
Xenbase Vilin,
A single residue differentiates between human cardiac and skeletal muscle Na+ channel slow inactivation.
2001,
Pubmed
,
Xenbase Wang,
Tryptophan substitution of a putative D4S6 gating hinge alters slow inactivation in cardiac sodium channels.
2005,
Pubmed Wang,
A mutation in segment I-S6 alters slow inactivation of sodium channels.
1997,
Pubmed Wang,
Clinical, genetic, and biophysical characterization of SCN5A mutations associated with atrioventricular conduction block.
2002,
Pubmed West,
A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation.
1992,
Pubmed
,
Xenbase Xiong,
Molecular motions of the outer ring of charge of the sodium channel: do they couple to slow inactivation?
2003,
Pubmed
,
Xenbase Yang,
Molecular basis of charge movement in voltage-gated sodium channels.
1996,
Pubmed Yang,
Evidence for voltage-dependent S4 movement in sodium channels.
1995,
Pubmed Yang,
How does the W434F mutation block current in Shaker potassium channels?
1997,
Pubmed
,
Xenbase Yellen,
An engineered cysteine in the external mouth of a K+ channel allows inactivation to be modulated by metal binding.
1994,
Pubmed Zhang,
A negatively charged residue in the outer mouth of rat sodium channel determines the gating kinetics of the channel.
2003,
Pubmed Zhou,
Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 A resolution.
2001,
Pubmed
