Potassium Channel Blockers Inhibit the Triggers of Attacks in the Calcium Channel Mouse Mutanttottering

Abstract

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 ␣ 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.

Aminopyridines Correct Early Dysfunction and Delay Neurodegeneration in a Mouse Model of Spinocerebellar Ataxia Type 1

“…A 45 min interval was used between injection and behavioral assessment or sacrifice and electrophysiological recordings to insure drug bioavailability. These dosages and delays were well tolerated and the most effective preventing dyskinesia attacks in tottering mice (Weisz et al, 2005). Chronic subcutaneous treatment was performed using 200 l Alzet miniosmotic pumps (model 2004; Durect Corporation) implanted subcutaneously in the back of the mice.…”

Episodic Ataxia Type 2

“…46 Another study showed that aminopyridines (4-AP; 3,4-DAP) effectively prevent attacks in tottering mice. 47 The leaner mouse mutant also harbors a homozygous spontaneous mutation in the gene encoding the voltageactivated Ca 2ϩ channel ␣1A subunit, the pore-forming subunit of P/Q-type Ca 2ϩ channels. 48 On the basis of this mutation, an out-of-frame splicing event in the carboxy terminus occurs which results in dramatic reductions in P-type Ca 2ϩ channel function in cerebellar Purkinje neurons.…”

“…These results suggest that the aminopyridines increase the threshold for attack initiation without mitigating the character of the attack. 47 From a clinical point of view, a prospective randomized controlled study is necessary to prove the short-and long-term effects of 4-AP and to compare them with ACTZ, which remains the standard treatment for EA 2.…”

Molecular Pathogenesis of Spinocerebellar Ataxia Type 6

“…4,46,47 Several studies suggest that the truncated subunits exhibit dominant inheritance by exerting a dominant negative effect on the wild-type P/Q current activity. 44,48,49 SCA6 is a progressive ataxic disorder caused by a trinucleotide repeat (CAG) expansion in exon 47 of the CACNA1A gene. 2 This repeat is translated into a polyglutamine expansion in the distal C-terminus of certain splice variants of the P/Q-type calcium channel ␣1A subunit.…”