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1 Internal Medicine, University of California, Davis, Davis, CA, USA
2 Pharmacology Department, Hebei Medical University, Shijiazhuang, China; Internal Medicine, University of California, Davis, Davis, CA, USA
* To whom correspondence should be addressed. E-mail: nchiamvimonvat{at}ucdavis.edu.
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 which 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 µ 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 delayed 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, MTSES, resulted in a reactivation profile from slow-inactivated state, which was indistinguishable from that of the wild-type channels. We proposed 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 region 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.
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