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Vol. 61, Issue 1, 136-141, January 2002

Structural Basis of Differences in Isoform-Specific Gating and Lidocaine Block between Cardiac and Skeletal Muscle Sodium Channels

Ronald A. Li, Irene L. Ennis, Gordon F. Tomaselli, and Eduardo Marbán

Institute of Molecular Cardiobiology, the Johns Hopkins University School of Medicine, Baltimore, Maryland

Voltage-gated Na+ channels underlie rapid conduction in heart and skeletal muscle. Cardiac sodium channels open and close over more negative potentials than do skeletal muscle sodium channels; heart channels are also more sensitive to lidocaine block. The structural basis of these differences is poorly understood. We mutated nine isoform-specific µ1 (rat skeletal muscle) channel residues in domain IV to those at equivalent locations in hH1 (human cardiac) channels. Channel constructs were expressed in tsA-201 cells and screened for changes in gating and lidocaine sensitivity. Only L1373E, located in the linker between the S1 and S2 transmembrane segments, shifted activation gating and use-dependent block by lidocaine toward that seen in hH1. The converse mutation, hH1-E1555L, shifted the phenotype of hH1 to resemble that of µ1. Therefore, we identified a previously unsuspected glutamate-to-leucine isoform-specific variant site (i.e., 1555 in hH1 and 1373 in µ1) that significantly influences gating and drug block in sodium channels. The identification of the residue at this position plays a major role in shaping the responses of sodium channels to voltage and to lidocaine, helping to rationalize the distinctive behavior of cardiac sodium channels.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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