QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, April 20, 2005, 25(16):4141-4145; doi:10.1523/JNEUROSCI.0098-05.2005

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Weisz, C. J. C. Articles by Hess, E. J. Search for Related Content PubMed PubMed Citation Articles by Weisz, C. J. C. Articles by Hess, E. J.

 Previous Article  |  Next Article 

BRIEF COMMUNICATION
Potassium Channel Blockers Inhibit the Triggers of Attacks in the Calcium Channel Mouse Mutant tottering

Catherine J. C. Weisz,¹ Robert S. Raike,¹ Luis E. Soria-Jasso,¹ and Ellen J. Hess^1,2

Departments of ¹Neurology and ²Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

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 ₁2.1 subunit of Ca_v2.1 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.

Key words: aminopyridine; channelopathy; caffeine; stress; cerebellum; tottering mouse; dystonia; potassium; calcium channel

---

Received Jan 10, 2005; revised March 16, 2005; accepted March 16, 2005.

This article has been cited by other articles:

				J.C. Jen, T.D. Graves, E.J. Hess, M.G. Hanna, R.C. Griggs, R.W. Baloh, and the CINCH investigators Primary episodic ataxias: diagnosis, pathogenesis and treatment Brain, October 1, 2007; 130(10): 2484 - 2493. [Abstract] [Full Text] [PDF]

				R. Kalla, S. Glasauer, U. Buttner, T. Brandt, and M. Strupp 4-Aminopyridine restores vertical and horizontal neural integrator function in downbeat nystagmus Brain, September 1, 2007; 130(9): 2441 - 2451. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help