XB-ART-35461
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.
???displayArticle.pubmedLink??? 16873407
???displayArticle.pmcLink??? PMC1890405
???displayArticle.link??? J Physiol
???displayArticle.grants??? [+]
R01 HL-72857 NHLBI NIH HHS , R01 HL072857-01A2 NHLBI NIH HHS , R01 HL50411 NHLBI NIH HHS , R01 HL072857 NHLBI NIH HHS , R01 HL050411 NHLBI NIH HHS
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