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Science 22 May 1992:
Vol. 256. no. 5060, pp. 1202 - 1205
DOI: 10.1126/science.256.5060.1202
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Articles

A Mutant of TTX-Resistant Cardiac Sodium Channels with TTX-Sensitive Properties

Jonathan Satin 1, John W. Kyle 2, Michael Chen 2, Peter Bell 2, Leanne L. Cribbs 2, Harry A. Fozzard 1, and Richard B. Rogart 2

1 Laboratory of Cardiac Electrophysiology, Departments of Medicine and Pharmacological and Physiological Sciences, and The Committee on Cell Physiology, The University of Chicago, MC-6094, 5841 South Maryland Avenue, Chicago, IL 60637
2 Laboratory of Molecular Neuro-Cardiology, Department of Medicine, and The Committee on Cell Physiology, The University of Chicago, MC-6094, 5841 South Maryland Avenue, Chicago, IL 60637

The cardiac sodium channel agr subunit (RHI) is less sensitive to tetrodotoxin (TTX) and saxitoxin (STX) and more sensitive to cadmium than brain and skeletal muscle (µl) isoforms. An RHI mutant, with Tyr substituted for Cys at position 374 (as in µl) confers three properties of TTX-sensitive channels: (i) greater sensitivity to TTX (730-fold); (ii) lower sensitivity to cadmium (28-fold); and (iii) altered additional block by toxin upon repetitive stimulation. Thus, the primary determinant of high-affinity TTX-STX binding is a critical aromatic residue at position 374, and the interaction may take place possibly through an ionized hydrogen bond. This finding requires revision of the sodium channel pore structure that has been previously suggested by homology with the potassium channel.


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