Abstract

Dystonia is a hyperkinetic disabling movement disorder. In the dt^sz hamster, a model of paroxysmal dystonia, pronounced antidystonic effects of the K_V7.2-5 potassium channel opener retigabine and aggravation of dystonia by a selective K_V7.2-5 blocker indicated a pathophysiological role of an abnormal expression of K_V7 channels. We therefore investigated the expression of K_V7 subunits in brains of dystonic hamsters. While K_V7.2 and K_V7.3 subunits were unaltered, lower K_V7.5 mRNA levels became evident in motor areas and in limbic structures of dystonic hamsters. The K_V7.2/3 subunit-preferring channel opener N-(6-chloropyridin-3-yl)-3,4- difluorobenzamide (ICA 27243; 10-30 mg/kg i.p.) failed to reduce the severity of dystonia in mutant hamsters, suggesting that the previously observed antidystonic action of retigabine is mediated by the activation of K_V7.5 channels. The experiments indicate a functional relevance for KV7.5 channels in paroxysmal dystonia. We suggest that compounds highly selective for subtypes of K_V7 channels, i.e. for K_V7.5, may provide new therapeutic approaches.

Keywords: animal model, dyskinesia, dystonia, ICA 27243, KCNQ, voltage-gated potassium channels.