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J. Biol. Chem., Vol. 279, Issue 11, 9681-9684, March 12, 2004

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ACCELERATED PUBLICATIONS

Gating Effects of Mutations in the Ca_v3.2 T-type Calcium Channel Associated with Childhood Absence Epilepsy^*

Houman Khosravani, Christophe Altier¶, Brett Simms, Kevin S. Hamming||, Terrance P. Snutch||**, Janette Mezeyova, John E. McRory, and Gerald W. Zamponi

From the Cellular and Molecular Neurobiology Research Group, University of Calgary, Calgary T2N 4N1, Canada, the ^||Biotechnology Laboratory, University of British Columbia, Vancouver V6T 1Z3, Canada, and NeuroMed Technologies Inc., Vancouver V6T 1Z4, Canada

Childhood absence epilepsy (CAE) is a type of generalized epilepsy observed in 2–10% of epileptic children. In a recent study by Chen et al. (Chen, Y., Lu, J., Pan, H., Zhang, Y., Wu, H., Xu, K., Liu, X., Jiang, Y., Bao, X., Yao, Z., Ding, K., Lo, W. H., Qiang, B., Chan, P., Shen, Y., and Wu, X. (2003) Ann. Neurol. 54, 239–243) 12 missense mutations were identified in the CACNA1H (Ca_v3.2) gene in 14 of 118 patients with CAE but not in 230 control individuals. We have functionally characterized five of these mutations (F161L, E282K, C456S, V831M, and D1463N) using rat Ca_v3.2 and whole-cell patch clamp recordings in transfected HEK293 cells. Two of the mutations, F161L and E282K, mediated an 10-mV hyperpolarizing shift in the half-activation potential. Mutation V831M caused a 50% slowing of inactivation relative to control and shifted half-inactivation potential 10 mV toward more depolarized potentials. Mean time to peak was significantly increased by mutation V831M but was unchanged for all others. No resolvable changes in the parameters of the IV relation or current kinetics were observed with the remaining mutations. The findings suggest that several of the Ca_v3.2 mutants allow for greater calcium influx during physiological activation and in the case of F161L and E282K can result in channel openings at more hyperpolarized (close to resting) potentials. This may underlie the propensity for seizures in patients with CAE.

Received for publication, January 7, 2004 , and in revised form, January 16, 2004.

^* This work was supported by operating grants from the Canadian Institutes of Health Research (CIHR) (to G. W. Z. and T. P. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Holds studentship awards from the Alberta Heritage Foundation for Medical Research (AHFMR) and the Savoy Foundation.

^¶ Holds postdoctoral Fellowship support from AHFMR and the Heart and Stroke Foundation of Canada.

^** CIHR Senior Investigator.

CIHR Investigator, a Senior Scholar of the AHFMR, and a Canada Research Chair in Molecular Neurobiology. To whom correspondence should be addressed: Dept. of Physiology and Biophysics, University of Calgary, 3330 Hospital Dr. NW, Calgary T2N 4N1, Canada. Tel.: 403-220-8687; Fax: 403-210-8106; E-mail. zamponi{at}ucalgary.ca.

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