The anticonvulsant retigabine suppresses neuronal KV 2-mediated currents

Abstract

Enhancement of neuronal M-currents, generated through KV 7.2-KV 7.5 channels, has gained much interest for its potential in developing treatments for hyperexcitability-related disorders such as epilepsy. Retigabine, a KV 7 channel opener, has proven to be an effective anticonvulsant and has recently also gained attention due to its neuroprotective properties. In the present study, we found that the auxiliary KCNE2 subunit reduced the KV 7.2-KV 7.3 retigabine sensitivity approximately 5-fold. In addition, using both mammalian expression systems and cultured hippocampal neurons we determined that low μM retigabine concentrations had off-target' effects on KV 2.1 channels which have recently been implicated in apoptosis. Clinical retigabine concentrations (0.3-3 μM) inhibited KV 2.1 channel function upon prolonged exposure. The suppression of the KV 2.1 conductance was only partially reversible. Our results identified KV 2.1 as a new molecular target for retigabine, thus giving a potential explanation for retigabine's neuroprotective properties.