Molecular determinants of voltage-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na+ channel α subunit

Vladimir Yarov-Yarovoy, Jacob Brown, Elizabeth M. Sharp, Jeff J. Clare, Todd Scheuer, William A. Catterall

Research output: Contribution to journalArticle

192 Citations (Scopus)

Abstract

Mutations of amino acid residues in the inner two-thirds of the S6 segment in domain III of the rat brain type IIA Na+ channel (G1460A to I1473A) caused pertodic positive and negative shifts in the voltage dependence of activation, consistent with an α-helix having one face on which mutations to alanine oppose activation. Mutations in the outer one-third of the IIIS6 segment all favored activation. Mutations in the inner half of IIIS6 had strong effects on the voltage dependence of inactivation from closed states without effect on open-state inactivation. Only three mutations had strong effects on block by local anesthetics and anticonvulsants. Mutations L1465A and I1469A decreased affinity of inactivated Na+ channels up to 8-fold for the anticonvulsant lamotrigine and its congeners 227c89, 4030w92, and 619c89 as well as for the local anesthetic etidocaine. N1466A decreased affinity of inactivated Na+ channels for the anticonvulsant 4030w92 and etidocaine by 3- and 8-fold, respectively, but had no effect on affinity of the other tested compounds. Leu-1465, Asn-1466, and Ile-1469 are located on one side of the IIIS6 helix, and muration of each caused a positive shift in the voltage dependence of activation. Evidently, these amino acid residues face the lumen of the pore, contribute to formarion of the high-affinity receptor site for pore-blocking drugs, and are involved in voltage-dependent activation and coupling to closed-state inactivation.

Original languageEnglish (US)
Pages (from-to)20-27
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number1
DOIs
StatePublished - Jan 5 2001
Externally publishedYes

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Chemical activation
Etidocaine
Mutation
Anticonvulsants
Electric potential
Pharmaceutical Preparations
Local Anesthetics
Amino Acids
S 6
Alanine
Rats
Brain
2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine

ASJC Scopus subject areas

  • Biochemistry

Cite this

Molecular determinants of voltage-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na+ channel α subunit. / Yarov-Yarovoy, Vladimir; Brown, Jacob; Sharp, Elizabeth M.; Clare, Jeff J.; Scheuer, Todd; Catterall, William A.

In: Journal of Biological Chemistry, Vol. 276, No. 1, 05.01.2001, p. 20-27.

Research output: Contribution to journalArticle

Yarov-Yarovoy, Vladimir ; Brown, Jacob ; Sharp, Elizabeth M. ; Clare, Jeff J. ; Scheuer, Todd ; Catterall, William A. / Molecular determinants of voltage-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na+ channel α subunit. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 1. pp. 20-27.
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abstract = "Mutations of amino acid residues in the inner two-thirds of the S6 segment in domain III of the rat brain type IIA Na+ channel (G1460A to I1473A) caused pertodic positive and negative shifts in the voltage dependence of activation, consistent with an α-helix having one face on which mutations to alanine oppose activation. Mutations in the outer one-third of the IIIS6 segment all favored activation. Mutations in the inner half of IIIS6 had strong effects on the voltage dependence of inactivation from closed states without effect on open-state inactivation. Only three mutations had strong effects on block by local anesthetics and anticonvulsants. Mutations L1465A and I1469A decreased affinity of inactivated Na+ channels up to 8-fold for the anticonvulsant lamotrigine and its congeners 227c89, 4030w92, and 619c89 as well as for the local anesthetic etidocaine. N1466A decreased affinity of inactivated Na+ channels for the anticonvulsant 4030w92 and etidocaine by 3- and 8-fold, respectively, but had no effect on affinity of the other tested compounds. Leu-1465, Asn-1466, and Ile-1469 are located on one side of the IIIS6 helix, and muration of each caused a positive shift in the voltage dependence of activation. Evidently, these amino acid residues face the lumen of the pore, contribute to formarion of the high-affinity receptor site for pore-blocking drugs, and are involved in voltage-dependent activation and coupling to closed-state inactivation.",
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