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Research ArticleArticle

Structural and Gating Changes of the Sodium Channel Induced by Mutation of a Residue in the Upper Third of IVS6, Creating an External Access Path for Local Anesthetics

Akihiko Sunami, Ian W. Glaaser and Harry A. Fozzard
Molecular Pharmacology April 2001, 59 (4) 684-691; DOI: https://doi.org/10.1124/mol.59.4.684
Akihiko Sunami
The Cardiac Electrophysiology Laboratories, Departments of Neurobiology, Pharmacology & Physiology, and Medicine, The University of Chicago, Chicago, Illinois
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Ian W. Glaaser
The Cardiac Electrophysiology Laboratories, Departments of Neurobiology, Pharmacology & Physiology, and Medicine, The University of Chicago, Chicago, Illinois
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Harry A. Fozzard
The Cardiac Electrophysiology Laboratories, Departments of Neurobiology, Pharmacology & Physiology, and Medicine, The University of Chicago, Chicago, Illinois
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Abstract

Membrane-impermeant quaternary amine local anesthetics QX314 and QX222 can access their binding site on the cytoplasmic side of the selectivity filter from the outside in native cardiac Na+channels. Mutation of domain IV S6 Ile-1760 of rat brain IIA Na+ channel or the equivalent (Ile-1575) in the adult rat skeletal muscle isoform (μ1) creates an artificial access path for QX. We examined the characteristics of mutation of μ1-I1575 and the resulting QX path. In addition to allowing external QX222 access, I1575A accelerated decay of Na+ current and shifted steady-state availability by −27 mV. I1575A had negligible effects on inorganic or organic cation selectivity and block by tetrodotoxin (TTX), saxitoxin (STX), or μ-conotoxin (μ-CTX). It exposed a site within the protein that binds membrane-permeant methanethiosulfonate ethylammonium (MTSEA), but not membrane-impermeant methanethiosulfonate ethyltrimethylammonium (MTSET) and methanethiosulfonate ethylsulfonate (MTSES). MTSEA binding abolished the QX path created by this mutation, without effects on toxin binding. The μ-CTX derivative R13N, which partially occluded the pore, had no effect on QX access. I1575A exposed two Cys residues because a disulfide bond was formed under oxidative conditions, but the exposed Cys residues are not those in domain IV S6, adjacent to Ile-1575. The Cys mutant I1575C was insensitive to external Cd2+ and MTS compounds (MTSEA, MTSET, MTSES), and substitution of Ile with a negatively charged residue (I1575E) did not affect toxin binding. Ile-1575 seems to be buried in the protein, and its mutation disrupts the protein structure to create the QX path without disturbing the outer vestibule and its selectivity function.

Footnotes

    • Received June 8, 2000.
    • Accepted December 19, 2000.
  • Send reprint requests to: Harry A. Fozzard, M.D., Cardiac Electrophysiology Laboratories (MC6094), University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637. E-mail:foz{at}hearts.bsd.uchicago.edu

  • This work was supported by National Institutes of Health Grant P01-HL20592.

  • Preliminary reports of this work have been published in abstract form [Sunami A, Dudley SC, Lipkind G, Fozzard HA (1998) A mutation of the sodium channel suggesting that domain IV S6 contributes to the outer vestibule. Biophys J 74:A398 and Sunami A, Lipkind G, Glaaser IW, Fozzard HA (1999) Characterizing structural rearrangement of the sodium channel outer vestibule induced by S6 mutants. Biophys J 76:A81].

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Molecular Pharmacology: 59 (4)
Molecular Pharmacology
Vol. 59, Issue 4
1 Apr 2001
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Research ArticleArticle

Structural and Gating Changes of the Sodium Channel Induced by Mutation of a Residue in the Upper Third of IVS6, Creating an External Access Path for Local Anesthetics

Akihiko Sunami, Ian W. Glaaser and Harry A. Fozzard
Molecular Pharmacology April 1, 2001, 59 (4) 684-691; DOI: https://doi.org/10.1124/mol.59.4.684

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Research ArticleArticle

Structural and Gating Changes of the Sodium Channel Induced by Mutation of a Residue in the Upper Third of IVS6, Creating an External Access Path for Local Anesthetics

Akihiko Sunami, Ian W. Glaaser and Harry A. Fozzard
Molecular Pharmacology April 1, 2001, 59 (4) 684-691; DOI: https://doi.org/10.1124/mol.59.4.684
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