Activation of expressed KCNQ potassium currents and native neuronal M-typepotassium currents by the anti-convulsant drug retigabine

Retigabine [D-23129; N-(2-amino-4-(4-fluorobenzylamino) phenyl) carbamic ac id ethyl ester] is a novel anticonvulsant compound that is now in clinical phase II development. It has previously been shown to enhance currents gene rated by KCNQ2/3 K+ channels when expressed in Chinese hamster ovary (CHO) cells (Main et al., 2000; Wickenden et al., 2000). In the present study, we have compared the actions of retigabine on KCNQ2/3 currents with those on currents generated by other members of the KCNQ family (homomeric KCNQ1, KC NQ2, KCNQ3, and KCNQ4 channels) expressed in CHO cells and on the native M current in rat sympathetic neurons [thought to be generated by KCNQ2/3 chan nels (Wang et al., 1998)]. Retigabine produced a hyperpolarizing shift of t he activation curves for KCNQ2/3, KCNQ2, KCNQ3, and KCNQ4 currents with dif ferential potencies in the following order: KCNQ3 > KCNQ2/3 > KCNQ2 > KCNQ4 , as measured either by the maximum hyperpolarizing shift in the activation curves or by the EC50 values. In contrast, retigabine did not enhance card iac KCNQ1 currents. Retigabine also produced a hyperpolarizing shift in the activation curve for native M channels in rat sympathetic neurons. The ret igabine-induced current was inhibited by muscarinic receptor stimulation, w ith similar agonist potency but 25% reduced maximum effect. In unclamped ne urons, retigabine produced a hyperpolarization and reduced the number of ac tion potentials produced by depolarizing current injections, without change in action potential configuration.