KCNQ4 channel activation by BMS-204352 and retigabine

Activation of potassium channels generally reduces cellular excitability, m aking potassium channel openers potential drug candidates for the treatment of diseases related to hyperexcitabilty such as epilepsy, neuropathic pain , and neurodegeneration. Two compounds, BMS-204352 and retigabine, presentl y in clinical trials for the treatment of stroke and epilepsy, respectively , have been proposed to exert their protective action via an activation of potassium channels. Here we show that KCNQ4 channels, stably expressed in H EK293 cells, were activated by retigabine and BMS-204352 in a reversible an d concentration-dependent manner in the concentration range 0.1-10 muM. Bot h compounds shifted the KCNQ4 channel activation curves towards more negati ve potentials by about 10 mV. Further, the maximal current obtainable at la rge positive voltages was also increased concentration-dependently by both compounds. Finally, a pronounced slowing of the deactivation kinetics was i nduced in particular by BMS-204352. The M-current blocker linopirdine inhib ited the baseline current, as well as the BMS-204352-induced activation of the KCNQ4 channels. KCNQ2, KCNQ2/Q3, and KCNQ3/Q4 channels were activated t o a similar degree as KCNQ4 channels by 10 muM of BMS-204352 and retigabine , respectively. The compounds are, thus, likely to be general activators of M-like currents. (C) 2001 Published by Elsevier Science Ltd.