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Molecular Pharmacology

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Research ArticleArticle

Novel Site on Sodium Channel α-Subunit Responsible for the Differential Sensitivity of Grayanotoxin in Skeletal and Cardiac Muscle

Takahiro Kimura, Kaoru Yamaoka, Eiji Kinoshita, Hiroshi Maejima, Tsunetsugu Yuki, Masuhide Yakehiro and Issei Seyama
Molecular Pharmacology October 2001, 60 (4) 865-872;
Takahiro Kimura
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Kaoru Yamaoka
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Eiji Kinoshita
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Hiroshi Maejima
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Tsunetsugu Yuki
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Masuhide Yakehiro
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Issei Seyama
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Abstract

We searched for sites on the α-subunit of the fast Na+channel responsible for the difference in GTX (grayanotoxin) sensitivity of the skeletal- and cardiac-muscle Na+current. cDNA clones, encoding the skeletal or cardiac isoforms of the α-subunit, were inserted into a mammalian expression vector and transiently transfected into human embryonic kidney cells. The expressed channels were measured using whole-cell patch-clamp techniques and examined for GTX sensitivity. As a measure of GTX sensitivity, we used relative chord conductance (ratio of maximum chord conductance of noninactivating GTX-modified Na+ currents to that of unmodified peak currents). Wild-type channels from skeletal muscle (μ1) were more sensitive to GTX modification than wild-type cardiac channels (rH1) by a factor of 1.6. To facilitate exploration of α-subunit sites determining GTX sensitivity, we used SHHH, a chimera of skeletal muscle (S) domain D1 and heart muscle (H) domains D2D3D4 with supernormal sensitivity to GTX I (1.5-fold of wild-type μ1). Successive replacement of Ser-251 (D1S4–S5 intracellular loop) and Ile-433 (D1S6 transmembrane segment), with corresponding rH1 residues Ala and Val, reduced, in a stepwise manner, the GTX sensitivity of the chimera and related mutants to that of wild-type rHl. We concluded that, in addition to Ile-433, known as the GTX-binding site, Ser-251 represents a novel site for GTX modification.

Footnotes

  • This work was supported by Grants 11470011 (to K.Y.) and 11770023 (to E.K.) from the Ministry of Education and Culture of Japan and by the research Grant 11C-1 (to I.S.) for cardiovascular diseases from the Ministry of Health and Welfare.

  • Abbreviations:
    GTX
    grayanotoxin
    D
    domain
    S
    segment
    HEK
    human embryonic kidney
    Po
    channel open probability
    I-V
    current-voltage
    INa
    Na+ current
    μ1
    α-subunit of rat skeletal muscle Na+ channel
    rH1
    α-subunit of rat heart Na+ channel
    • Received April 23, 2001.
    • Accepted June 13, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 60 (4)
Molecular Pharmacology
Vol. 60, Issue 4
1 Oct 2001
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Research ArticleArticle

Novel Site on Sodium Channel α-Subunit Responsible for the Differential Sensitivity of Grayanotoxin in Skeletal and Cardiac Muscle

Takahiro Kimura, Kaoru Yamaoka, Eiji Kinoshita, Hiroshi Maejima, Tsunetsugu Yuki, Masuhide Yakehiro and Issei Seyama
Molecular Pharmacology October 1, 2001, 60 (4) 865-872;

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Research ArticleArticle

Novel Site on Sodium Channel α-Subunit Responsible for the Differential Sensitivity of Grayanotoxin in Skeletal and Cardiac Muscle

Takahiro Kimura, Kaoru Yamaoka, Eiji Kinoshita, Hiroshi Maejima, Tsunetsugu Yuki, Masuhide Yakehiro and Issei Seyama
Molecular Pharmacology October 1, 2001, 60 (4) 865-872;
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