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| Gating effects of mutations in the Ca(v)3.2 T-type calcium channel associated with childhood absence epilepsy |
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| Author(s): Khosravani H, Altier C, Simms B, Hamming KS, Snutch TP, Mezeyova J, McRory JE, Zamponi GW |
| Source: JOURNAL OF BIOLOGICAL CHEMISTRY Volume: 279 Issue: 11 Pages: 9681-9684 Published: MAR 12 2004 |
| Times Cited: 59 References: 34 |
| 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 similar to10-mV hyperpolarizing shift in the half-activation potential. Mutation V831M caused a similar to 50% slowing of inactivation relative to control and shifted half-inactivation potential similar to 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 Cav3.2 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Zamponi, GW (reprint author), Univ Calgary, Dept Physiol & Biophys, Cellular & Mol Neurobiol Res Grp, 3330 Hosp Dr NW, Calgary, AB T2N 4N1 Canada |
Addresses:
1. Univ Calgary, Dept Physiol & Biophys, Cellular & Mol Neurobiol Res Grp, Calgary, AB T2N 4N1 Canada
2. Univ British Columbia, Biotechnol Lab, Vancouver, BC V6T 1Z3 Canada
3. NeuroMed Technol Inc, Vancouver, BC V6T 1Z4 Canada |
| Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA |
| Subject Category: Biochemistry & Molecular Biology |
| IDS Number: 800TK |
| ISSN: 0021-9258 |
| DOI: 10.1074/jbc.C400006200 |
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