title: Lower KV7.5 Potassium Channel Subunit Expression in an Animal Model of Paroxysmal Dystonia.
abstract: Dystonia is a hyperkinetic disabling movement disorder. In the dt(sz) hamster, a model of paroxysmal dystonia, pronounced antidystonic effects of the KV7.2-5 potassium channel opener retigabine and aggravation of dystonia by a selective KV7.2-5 blocker indicated a pathophysiological role of an abnormal expression of KV7 channels. We therefore investigated the expression of KV7 subunits in brains of dystonic hamsters. While KV7.2 and KV7.3 subunits were unaltered, lower KV7.5 mRNA levels became evident in motor areas and in limbic structures of dystonic hamsters. The KV7.2/3 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 KV7.5 channels. The experiments indicate a functional relevance for KV7.5 channels in paroxysmal dystonia. We suggest that compounds highly selective for subtypes of KV7 channels, i.e. for KV7.5, may provide new therapeutic approaches.
authors.affiliation: Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universität Berlin, Koserstr. 20, 14195 Berlin, Germany. svenja.sander@fu-berlin.de.
authors.forename: Svenja E
authors.initials: SE
authors.lastname: Sander
authors.forename: Mustansir
authors.initials: M
authors.lastname: Diwan
authors.forename: Roger
authors.initials: R
authors.lastname: Raymond
authors.forename: José N
authors.initials: JN
authors.lastname: Nobrega
authors.forename: Angelika
authors.initials: A
authors.lastname: Richter
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D006224:Cricetinae; D004195:Disease Models, Animal; D004421:Dystonia / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D051656:KCNQ Potassium Channels / Q000096:biosynthesis* / Q000235:genetics; D008647:Mesocricetus; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics
chemical_list: D051656:KCNQ Potassium Channels; C412231:KCNQ5 protein, human; D021122:Protein Subunits