title: The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits.
abstract: Retigabine (D-23129) is a novel antiepileptic compound with broad spectrum and potent anticonvulsant properties, both in vitro and in vivo. The compound was shown to activate a K(+) current in neuronal cells. The pharmacology of the induced current displays concordance with the published pharmacology of the M-channel, which recently was correlated to the KCNQ2/3 K(+) channel heteromultimere. We examined the effect of retigabine on KCNQ2/3 expressed in Chinese hamster ovary cells. The compound concentration-dependently activated a K(+) current in transfected cells clamped at -50 mV. The activation was 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 and could be partially blocked by the M-channel antagonist linopirdine. The data display that retigabine is the first described M-channel agonist and 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 hereditary epilepsy syndrome, retigabine may be the first anticonvulsant to directly target the deficit observed in a channelopathy.
authors.affiliation: Department of Pharmacology, Arzneimittelwerk Dresden GmbH, Corporate R&D, ASTA Medica Group, Meibetaner Strasse 35, D-01445, Radebeul, Germany. dr_chris.rundfeldt@astamedica.de
authors.forename: C
authors.initials: C
authors.lastname: Rundfeldt
authors.forename: R
authors.initials: R
authors.lastname: Netzer
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D016466:CHO Cells; D002219:Carbamates / Q000494:pharmacology*; D006224:Cricetinae; D006801:Humans; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D018408:Patch-Clamp Techniques; D010655:Phenylenediamines / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D014162:Transfection
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D051659:KCNQ3 Potassium Channel; C496916:KCNQ3 protein, human; D010655:Phenylenediamines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C101866:ezogabine