title: Structural basis of differences in isoform-specific gating and lidocaine block between cardiac and skeletal muscle sodium channels.
abstract: 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 micro1 (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 micro1. Therefore, we identified a previously unsuspected glutamate-to-leucine isoform-specific variant site (i.e., 1555 in hH1 and 1373 in micro1) 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.
authors.affiliation: Institute of Molecular Cardiobiology, the Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Li
authors.forename: Irene L
authors.initials: IL
authors.lastname: Ennis
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Tomaselli
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
mesh_terms: D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008012:Lidocaine / Q000737:chemistry / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000737:chemistry / Q000502:physiology
chemical_list: D000596:Amino Acids; D020033:Protein Isoforms; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008012:Lidocaine