Key result
Disopyramide acts as a low-potency open channel blocker of Kv1.5 from the cytoplasmic side, interacting primarily with the Val512 residue, where mutation to Ala increased the IC50 22-fold.
Disopyramide acts as an open channel blocker of Kv1.5 channels from the cytoplasmic side, primarily interacting with the Val512 residue in the central cavity.
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Offers mechanistic insight into disopyramide but should not yet change practice; leaves open clinical relevance of Kv1.5 blockade.
Kv1.5 is considered to be a potential molecular target for treatment of atrial fibrillation or flutter. Disopyramide is widely used in the treatment of atrial flutter and/or atrial fibrillation. The present study was undertaken to characterize the effects of disopyramide on currents mediated by Kv1.5 channels and to determine the putative binding site involved in the inhibitory effects of disopyramide. Experiments were carried out on wild-type and site directed mutated hKv1.5 channels expressed on HEK 293 cells using the patch-clamp technique. Disopyramide acting from the cytoplasmic side of the membrane produced blocking effects on Kv1.5 that exhibited several features typical of an open channel blocker. Ala-scanning mutagenesis of the Kv1.5 pore domain combined with macroscopic current analysis suggested that disopyramide interacted only with the Val512 residue that faces to the central cavity of the channel. Mutation of this key residue to Ala caused marked change in the IC(50) of disopyramide (22-fold). The single interaction between disopyramide and Val512 in the PVP region is able to change the mechanism of channel closure, reproducing the "foot-in-the-door" phenomenon.
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Aréchiga et al. (2008) studied In vitro Kv1.5 channel block. Disopyramide vs. Control (drug-free) was evaluated on Kv1.5 current inhibition (IC50). Disopyramide acts as a low-potency open channel blocker of Kv1.5 from the cytoplasmic side, interacting primarily with the Val512 residue, where mutation to Ala increased the IC50 22-fold.
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