The cardiac sodium channel: Gating function and molecular pharmacology

Cardiac sodium (Na) channels are dynamic molecules that undergo rapid struc tural changes in response to the changing electrical field in the myocardiu m. Inherited mutations in SCN5A, the gene encoding the cardiac Na channel, provoke life-threatening cardiac arrhythmias, often by modifying these volt age-dependent conformational changes. These disorders (i.e., the long QT sy ndrome and Brugada syndrome) may serve as valuable models for understanding the mechanistic linkages between Na channel dysfunction and cardiac arrhyt hmias in more common, acquired conditions such as cardiac ischemia. In addi tion, the balance between therapeutic and adverse effects from Na channel b lockade by antiarrhythmic compounds may be shifted by subtle alterations in Na channel function. This review examines recent studies that tie key loci in the Na channel primary sequence to its dynamic function, while examinin g the emerging themes linking Na channel structure, function, and pharmacol ogy to inherited and acquired disorders of cardiac excitability. (C) 2001 A cademic Press.