PT  - JOURNAL ARTICLE
AU  - Ronald A. Li
AU  - Irene L. Ennis
AU  - Gordon F. Tomaselli
AU  - Eduardo Marbán
TI  - Structural Basis of Differences in Isoform-Specific Gating and Lidocaine Block between Cardiac and Skeletal Muscle Sodium Channels
AID  - 10.1124/mol.61.1.136
DP  - 2002 Jan 01
TA  - Molecular Pharmacology
PG  - 136--141
VI  - 61
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/61/1/136.short
4100  - http://molpharm.aspetjournals.org/content/61/1/136.full
SO  - Mol Pharmacol2002 Jan 01; 61
AB  - 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.