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 alpha and beta 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 alpha and beta 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.
Abitbol
I
I
Department of Neurobiology, The Weizmann Institute of Science, 76100 Rehovot, Israel.
Peretz
A
A
Lerche
C
C
Busch
A E
AE
Attali
B
B
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D006801:Humans; D008528:Mefenamic Acid / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D016297:Mutagenesis, Site-Directed; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014981:Xenopus
D015221:Potassium Channels; D008528:Mefenamic Acid; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid