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. M any 'channelopathies' are accounted for by a dominant-lethal suppression of potassium channel function. In the cardiac I-KS channel complex comprising the a and beta subunits, KvLQT1 and IsK, respectively, several mutations l ead to a dominant-negative loss of channel function. These defects are resp onsible for a human cardiovascular disease called long QT (LQT) syndrome. H ere 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 IKS channel gating in otherwise inactive IsK C-ter minal mutants, including the naturally occurring LQT5 mutant, D76N, Our dat a support a model in which allosteric interactions exist between the extrac ellular and intracellular boundaries of the IsK transmembrane segment as we ll as between domains of the alpha and beta subunits, Disruption of this al losteric interplay impedes slow activation gating, decreases current amplit ude and restores channel inactivation, Owing to allosteric interactions, st ilbene 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.