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Am J Physiol Cell Physiol 284: C1247-C1254, 2003. First published January 22, 2003; doi:10.1152/ajpcell.00471.2002
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Vol. 284, Issue 5, C1247-C1254, May 2003

A negatively charged residue in the outer mouth of rat sodium channel determines the gating kinetics of the channel

Zhao Zhang1, Yanfang Xu1,3, Pei Hong Dong1, Dipika Sharma1, and Nipavan Chiamvimonvat1,2

1 Division of Cardiovascular Medicine, University of California, Davis 95616; 2 Department of Veterans Affairs, Northern California Health Care System, Mather, California 95655; and 3 Pharmacology Department, Hebei Medical University, Shijiazhuang, 050017 Hebei, China

Previous studies using combined techniques of site-directed mutagenesis and electrophysiology of voltage-gated Na+ channels have demonstrated that there are significant overlaps in the regions that are important for the two fundamental properties of the channels, namely gating and permeation. We have previously shown that a pore-lining residue, W402 in S5-S6 region (P loop) in domain I of the µ1 skeletal muscle Na+ channel, was important in the gating of the channel. Here, we determined the role of an adjacent pore-lining negatively charged residue (E403) in channel gating. Charge neutralization or substitution with positively charged side chain at this position resulted in a marked delay in the rate of recovery from slow inactivation. Indeed, the fast inactivation process appeared intact. Restoration of the negatively charged side chain with a sulfhydryl modifier, MTS-ethylsulfonate, resulted in a reactivation profile from a slow-inactivated state, which was indistinguishable from that of the wild-type channels. We propose an additional functional role for the negatively charged residue. Assuming no major changes in the pore structure induced by the mutations, the negatively charged residue E403 may work in concert with other pore regions during recovery from slow inactivation of the channel. Our data represent the first report indicating the role of negative charge in the slow inactivation of the voltage-gated Na+ channel.

sodium channel; site-directed mutagenesis; slow inactivation


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