Key result
Verapamil preferentially blocked the human Kv1.5 channel in its open state with an IC50 of 2.4 mM, and this blockade was significantly attenuated by mutations in the pore region.
Why the study?
Verapamil prolongs the human atrial effective refractory period to prevent atrial arrhythmias, but the underlying molecular and electrophysiological mechanism on the hKv1.5 channel was not defined.
Verapamil acts as an open-channel blocker of the hKv1.5 channel by binding to specific amino acids within the pore region, providing a structural basis for its atrial-specific antiarrhythmic effects.
Supports mechanistic studies of verapamil on atrial potassium channels; leaves open therapeutic implications for atrial fibrillation.
BACKGROUND/AIMS: channel antagonist verapamil prolongs the effective refractory period (ERP) of human atrium, which appears to contribute to the efficacy of verapamil in preventing reentrant-based atrial arrhythmias including atrial fibrillation. This study was designed to investigate the molecular and electrophysiological mechanism underlying the action of verapamil on human Kv1.5 (hKv1.5) channel that determines action potential duration and ERP in human atrium. METHODS: Site-directed mutagenesis created 10 single-point mutations within pore region of hKv1.5 channel. Wholecell patch-clamp method investigated the effect of verapamil on wild-type and mutant hKv1.5 channels heterologously expressed in Chinese hamster ovary cells. Docking simulation was conducted using open-state homology model of hKv1.5 channel pore. RESULTS: of 2.4±0.6 μM (n = 6). The blocking effect of verapamil was significantly attenuated in T479A, T480A, I502A, V505A, I508A, L510A, V512A and V516A mutants, compared with wild-type hKv1.5 channel. Computer docking simulation predicted that verapamil is positioned within central cavity of channel pore and has contact with Thr479, Thr480, Val505, Ile508, Ala509, Val512, Pro513 and Val516. CONCLUSION: Verapamil acts as an open-channel blocker of hKv1.5 channel, presumably due to direct binding to specific amino acids within pore region of hKv1.5 channel, such as Thr479, Thr480, Val505, Ile508, Val512 and Val516. This blocking effect of verapamil on hKv1.5 channel appears to contribute at least partly to prolongation of atrial ERP and resultant antiarrhythmic action on atrial fibrillation in humans.
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Ding et al. (2019) studied this question. Verapamil vs. Control (absence of verapamil) was evaluated on IC50 of hKv1.5 channel block. Verapamil preferentially blocked the human Kv1.5 channel in its open state with an IC50 of 2.4 mM, and this blockade was significantly attenuated by mutations in the pore region.
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