Potassium channel blockers inhibit the triggers of attacks in the calcium channel mouse mutant tottering.
Humans with the disorder episodic ataxia type 2 (EA2) and the tottering mouse mutant exhibit episodic attacks induced by emotional and chemical stress. Both the human and mouse disorders result from mutations in CACNA1A, the gene encoding the alpha(1)2.1 subunit of Ca(v)2.1 voltage-gated calcium channels. These mutations predict reduced calcium currents, particularly in cerebellar Purkinje cells, where these channels are most abundant. 4-Aminopyridine (4-AP), a nonselective blocker of K(v) voltage-gated potassium channels, alleviates attacks of ataxia in EA2 patients. To test the specificity of the effect for K(v) channels, aminopyridine analogs were assessed for their ability to ameliorate attacks of dyskinesia in tottering mice. 4-AP and 3,4-diaminopyridine (3,4-DiAP), which have relatively high affinities for K(v) channels, reduced the frequency of restraint- and caffeine-induced attacks. Furthermore, microinjection of 3,4-DiAP into the cerebellum completely blocked attacks in tottering mice. Other aminopyridine analogs reduced attack frequency but, consistent with their lower affinities for K(v) channels, required comparatively higher doses. These results suggest that aminopyridines block tottering mouse attacks via cerebellar K(v) channels. That both stress- and caffeine-induced attacks were blocked by aminopyridines suggests that these triggers act via similar mechanisms. Although 4-AP and 3,4-DiAP were effective in preventing attacks in tottering mice, these compounds did not affect the severity of "breakthrough" attacks that occurred in the presence of a drug. These results suggest that the aminopyridines increase the threshold for attack initiation without mitigating the character of the attack, indicating that attack initiation is mediated by mechanisms that are independent of the neurological phenotype.
Weisz
Catherine J C
CJ
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Raike
Robert S
RS
Soria-Jasso
Luis E
LE
Hess
Ellen J
EJ
D015761:4-Aminopyridine / Q000008:administration & dosage* / Q000737:chemistry; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002110:Caffeine / Q000009:adverse effects; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type / Q000235:genetics*; D020907:Calcium Channels, Q-Type / Q000235:genetics*; D002531:Cerebellum / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020820:Dyskinesias / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008845:Microinjections / Q000379:methods; D009154:Mutation; D026902:Potassium Channel Blockers / Q000008:administration & dosage*
D015761:4-Aminopyridine; D002110:Caffeine; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D026902:Potassium Channel Blockers