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 poody understood. We mutated nine isoform-specific υ1 (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 hill to resemble that of υ1. Therefore, we identified a previously unsuspected glutamate-to-leucine isoform-specific variant site (i.e., 1555 in hH1 and 1373 in υ1) 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.
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