title: Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy.
abstract: 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(v)3.2) 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(v)3.2 and whole-cell patch clamp recordings in transfected HEK293 cells. Two of the mutations, F161L and E282K, mediated an approximately 10-mV hyperpolarizing shift in the half-activation potential. Mutation V831M caused a approximately 50% slowing of inactivation relative to control and shifted half-inactivation potential approximately 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(v)3.2 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.
authors.affiliation: Cellular and Molecular Neurobiology Research Group, University of Calgary, Canada.
authors.forename: Houman
authors.initials: H
authors.lastname: Khosravani
authors.forename: Christophe
authors.initials: C
authors.lastname: Altier
authors.forename: Brett
authors.initials: B
authors.lastname: Simms
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Hamming
authors.forename: Terrance P
authors.initials: TP
authors.lastname: Snutch
authors.forename: Janette
authors.initials: J
authors.lastname: Mezeyova
authors.forename: John E
authors.initials: JE
authors.lastname: McRory
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Zamponi
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000235:genetics* / Q000502:physiology*; D002460:Cell Line; D004594:Electrophysiology; D004832:Epilepsy, Absence / Q000235:genetics*; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014162:Transfection
chemical_list: C479952:CACNA1H protein, human; D020747:Calcium Channels, T-Type; D012333:RNA, Messenger; D002118:Calcium