Spinocerebellar ataxia (SCA) 6 is caused by small expansion of a polyglutamine sequence, encoded by CAG trinucleotide repeats, at the C-terminal end of the human Ca V2.1 (P/Q-type) Ca 2+ channel α 12.1 subunit and it manifests itself as slowly progressive cerebellar ataxia. To elucidate the pathogenic mechanisms underlying SCA6, we introduced CAG repeats of various lengths into the Ca 2+ channel α 12.1 subunit cDNA and expressed them in baby hamster kidney cells stably expressing the auxiliary subunits (α 2δ and β 4). The occurrence of cell death differed between cells transfected with the normal and mutant Ca 2+ channels under the condition of serum starvation plus potassium-induced depolarization, and Cdk inhibition elucidated the differences more clearly. The Ca V2.1 (P/Q-type) Ca 2+ channel-specific blocker ω-agatoxin IVA abolished the cell-death-preventing effect of the normal Ca 2+ channel. Together with our previous finding that the polyglutamine expansion in SCA6 interferes with the Ca 2+ channel to reduce Ca 2+ influx, these results indicate that impaired function of the mutant Ca 2+ channels rendered them unable to prevent cell death.
- Ca 2.1 Ca channel
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