Characterization of neurological CaィイD12+ィエD1 channel mutant mice.

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P/Q-type voltage-dependent CaィイD12+ィエD1 channels are markedly abundant in the nervous system. We have characterized functional abnormality of the P/Q-type channels elicited by the αィイD21AィエD2,. mutations, tottering (tg) and leaner (tgィイD1laィエD1). Comparison of properties of the native and recombinant mutant channels suggests that single tottering mutations are directly responsible for the neuropathic phenotypes of reduction in current density and deviations in gating behavior, which lead to neuronal death and cerebellar atrophy. The ataxic mouse mutation, rolling Nagoya (tgィイD1rolィエD1), in the αィイD21AィエD2, gene leads to a charge-neutralizing arginine-to-glycine substitution at position 1262 in the voltage sensor-forming segment S4 in repeat III. Functional changes induced by the tgィイD1rolィエD1 mutation in the recombinant αィイD21AィエD2 channel indicate that a gating charge defect in the voltage sensor of P/Q-type CaィイD12+ィエD1 channels is the direct consequence of the tgィイD1rolィエD1 mutation … More . Furthermore, in tgィイD1rolィエD1 mice, the abnormal P-type channel significantly impairs integrative properties of Purkinje neurons, resulting in locomotor deficits.Spinocerebellar ataxia 6 (SCA6) is caused by expansion of a polyglutamine stretch, encoded by a CAG trinucleotide repea1 in the human P/Q type CaィイD12+ィエD1 channel αィイD21AィエD2 subunit. The CaィイD12+ィエD1 channels with 30 or 40 polyglutamines exhibited an 8 mV hyperpolarizing shift in the voltage dependence of inactivation, which considerably reduces the available channel population at a resting membrane potential. The results strongly suggest that polyglutamine expansion in SCA6 leads to neuronal death and cerebellar atrophy through reduction in CaィイD12+ィエD1 influx into Purkinje cells and other neurons, besides the widely accepted notion that polyglutamine stretches exert toxic effects by forming aggregates.Our research also provided evidence that cytoplasmic loop between repeats II and III of N-type channels is a regulatory site for Gβγ and the C-termini of P/Q and N-types for Gα. Less