The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits

Retigabine (D-23129) is a novel antiepileptic compound with broad spectrum and potent anticonvulsant properties, both in vitro and in vivo. The compou nd was shown to activate a K+ current in neuronal cells. The pharmacology o f the induced current displays concordance with the published pharmacology of the M-channel, which recently was correlated to the KCNQ2/3 K+ channel h eteromultimere. We examined the effect of retigabine on KCNQ2/3 expressed i n Chinese hamster ovary cells. The compound concentration-dependently activ ated a K+ current in transfected cells clamped at -50 mV. The activation wa s induced by a shift of the opening threshold to more negative potentials. The effect was not mediated by an interaction with the cAMP modulatory site a nd could be partially blocked by the M-channel antagonist linopirdine. T he data display that retigabine is the first described M-channel agonist an d support the hypothesis that M-channel agonism is a new mode of action for anticonvulsant drugs. Since the function of this channel is reduced in a h ereditary epilepsy syndrome, retigabine may be the first anticonvulsant to directly target the deficit observed in a channelopathy. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.