Stilbenes and fenamates rescue the loss of I KS channel function induced by an LQT5 mutation and other IsK mutants

Genetic and physiological studies have established a link between potassium channel dysfunction and a number of neurological and muscular disorders. Many ‘channelopathies’ are accounted for by a dominant‐lethal suppression of potassium channel function. In the cardiac I KS channel complex comprising the α and β subunits, KvLQT1 and IsK, respectively, several mutations lead to a dominant‐negative loss of channel function. These defects are responsible for a human cardiovascular disease called long QT (LQT) syndrome. Here we show that binding of I KS channel activators, such as stilbenes and fenamates, to an extracellular domain flanking the human IsK transmembrane segment, restores normal I KS channel gating in otherwise inactive IsK C‐terminal mutants, including the naturally occurring LQT5 mutant, D76N. Our data support a model in which allosteric interactions exist between the extracellular and intracellular boundaries of the IsK transmembrane segment as well as between domains of the α and β subunits. Disruption of this allosteric interplay impedes slow activation gating, decreases current amplitude and restores channel inactivation. Owing to allosteric interactions, stilbene and fenamate compounds can rescue the dominant‐negative suppression of I KS produced by IsK mutations and thus, may have important therapeutic relevance for LQT syndrome.