PMID:10908603

Citation	Mori, Y, Wakamori, M, Oda, S, Fletcher, CF, Sekiguchi, N, Mori, E, Copeland, NG, Jenkins, NA, Matsushita, K, Matsuyama, Z and Imoto, K (2000) Reduced voltage sensitivity of activation of P/Q-type Ca2+ channels is associated with the ataxic mouse mutation rolling Nagoya (tg(rol)). J. Neurosci. 20:5654-62
Abstract	Recent genetic analyses have revealed an important association of the gene encoding the P/Q-type voltage-dependent Ca(2+) channel alpha(1A) subunit with hereditary neurological disorders. We have identified the ataxic mouse mutation, rolling Nagoya (tg(rol)), in the alpha(1A) gene that leads to a charge-neutralizing arginine-to-glycine substitution at position 1262 in the voltage sensor-forming segment S4 in repeat III. Ca(2+) channel currents in acutely dissociated Purkinje cells, where P-type is the dominant type, showed a marked decrease in slope and a depolarizing shift by 8 mV of the conductance-voltage curve and reduction in current density in tg(rol) mouse cerebella, compared with those in wild-type. Compatible functional change was induced by the tg(rol) mutation in the recombinant alpha(1A) channel, indicating that a defect in voltage sensor of P/Q-type Ca(2+) channels is the direct consequence of the tg(rol) mutation. Furthermore, somatic whole-cell recording of mutant Purkinje cells displayed only abortive Na(+) burst activity and hardly exhibited Ca(2+) spike activity in cerebellar slices. Thus, in tg(rol) mice, reduced voltage sensitivity, which may derive from a gating charge defect, and diminished activity of the P-type alpha(1A) Ca(2+) channel significantly impair integrative properties of Purkinje neurons, presumably resulting in locomotor deficits.
Links	PubMed
Keywords	Action Potentials/genetics; Alleles; Amino Acid Substitution; Animals; Ataxia/genetics; Ataxia/physiopathology; Calcium Channels, N-Type/chemistry; Calcium Channels, N-Type/genetics; Calcium Channels, N-Type/metabolism; Electric Stimulation; Electrophysiology; Female; Ion Channel Gating/genetics; Male; Mice; Mice, Congenic; Mice, Inbred C3H; Mice, Neurologic Mutants; Phenotype; Protein Structure, Tertiary; Purkinje Cells/chemistry; Purkinje Cells/physiology; Recombinant Proteins/chemistry; Recombinant Proteins/genetics
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