Inherited sodium channelopathies: a continuum of channel dysfunction

Voltage-gated sodium channels are transmembrane proteins that produce the ionic current responsible for the rising phase of the cardiac action potential and play a fundamental role in the initiation, propagation, and maintenance of normal cardiac rhythm. Inherited mutations in SCN5A, the gene encoding the pore-forming subunit of the cardiac Na+ channel, have been associated with distinct cardiac rhythm syndromes: the congenital long QT syndrome, Brugada syndrome, and isolated conduction disease. Electrophysiologic characterization of heterologously expressed mutant Na+ channels have revealed gating defects that, in many cases, can explain the distinct phenotype associated with the rhythm disorder. However, recent studies have revealed significant overlap between aberrant rhythm phenotypes, and single mutations have been identified that evoke multiple rhythm disorders with common gating lesions. These new insights enhance understanding of the structure-function relationships of voltage-gated Na+ channels, and also highlight the complexities involved in linking single mutations, ion-channel behavior, and cardiac rhythm.