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J. Biol. Chem., Vol. 277, Issue 38, 35393-35401, September 20, 2002
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From the Department of Pharmacology, University of Washington,
Seattle, Washington 98195-7280
Alanine-scanning mutagenesis of transmembrane
segments IS6 and IIS6 of the rat brain Nav1.2 channel
Role of Amino Acid Residues in Transmembrane Segments IS6 and
IIS6 of the Na+ Channel
Subunit in
Voltage-dependent Gating and Drug Block*
subunit identified mutations N418A in IS6 and L975A in IIS6 as
causing strong positive shifts in the voltage dependence of activation.
In contrast, mutations V424A in IS6 and L983A in IIS6 caused strong
negative shifts. Most IS6 mutations opposed inactivation from closed
states, but most IIS6 mutations favored such inactivation. Mutations
L421C and L983A near the intracellular ends of IS6 and IIS6,
respectively, exhibited significant sustained Na+ currents
at the end of 30-ms depolarizations, indicating a role for these
residues in Na+ channel fast inactivation. These residues,
in combination with residues at the intracellular end of IVS6, are well
situated to form an inactivation gate receptor. Mutation I409A in IS6
reduced the affinity of the local anesthetic etidocaine for the
inactivated state by 6-fold, and mutations I409A and N418A reduced
use-dependent block by etidocaine. No IS6 or IIS6 mutations
studied affected inactivated-state affinity or
use-dependent block by the neuroprotective drug
sipatrigine (compound 619C89). These results suggest that the
local anesthetic receptor site is formed primarily by residues in
segments IIIS6 and IVS6 with the contribution of a single amino acid in
segment IS6.
*
This work was supported by Research Grant R-01 N515751 from
the National Institutes of Health (to W. A. C.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Pharmacology,
P. O. Box 357280, Seattle, WA 98195-7280. Tel.: 206-543-1925; Fax:
206-543-3882; E-mail: wcatt@u.washington.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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