title: KCa channels as therapeutic targets in episodic ataxia type-2.
abstract: Episodic ataxia type-2 (EA2) is an inherited movement disorder caused by mutations in the gene encoding the Ca(v)2.1alpha1 subunit of the P/Q-type voltage-gated calcium channel that result in an overall reduction in the P/Q-type calcium current. A consequence of these mutations is loss of precision of pacemaking in cerebellar Purkinje cells. This diminished precision reduces the information encoded by Purkinje cells and is thought to contribute to symptoms associated with this disorder. The loss of the precision of pacemaking in EA2 is the consequence of reduced activation of calcium-dependent potassium channels (K(Ca)) by the smaller calcium current and in vitro can be pharmacologically restored by K(Ca) activators. We used a well established mouse model of EA2, the tottering (tg/tg) mouse, to examine the potential therapeutic utility of one such Food and Drug Administration (FDA)-approved compound, chlorzoxazone (CHZ). Compared with wild-type Purkinje cells, we found the firing rate of tg/tg Purkinje cells in acutely prepared cerebellar slices to be very irregular. Bath application of CHZ successfully restored the precision of pacemaking in a dose-dependent manner. Oral administration of CHZ to tg/tg mice improved their baseline motor performance and reduced the severity, frequency, and duration of episodes of dyskinesia without producing any adverse effects. We propose the use of CHZ, which is currently FDA approved as a muscle relaxant, as a safe and novel treatment of EA2.
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Alviña
authors.forename: Kamran
authors.initials: K
authors.lastname: Khodakhah
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002524:Cerebellar Ataxia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002531:Cerebellum / Q000473:pathology; D002753:Chlorzoxazone / Q000008:administration & dosage* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020820:Dyskinesias / Q000150:complications / Q000188:drug therapy; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D026902:Potassium Channel Blockers / Q000008:administration & dosage* / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011689:Purkinje Cells / Q000187:drug effects / Q000502:physiology; D013315:Stress, Psychological / Q000150:complications / Q000209:etiology
chemical_list: D001562:Benzimidazoles; D047908:Intracellular Signaling Peptides and Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C105159:SH3GL1 protein, human; C086491:NS 1619; D002753:Chlorzoxazone