Spinocerebellar ataxia type 6 mutation alters P-type calcium channel function

Abnormal CAG repeat expansion in the alpha 1A voltage-dependent calcium channel gene is associated with spinocerebellar ataxia type 6, an autosomal dominant cerebellar ataxia with a predominant loss of the Purkinje cell. A reverse transcriptase-polymerase chain reaction analysis of mRNA from mouse Purkinje cells revealed a predominant expression of the alpha 1A channel lacking an asparagine-proline (NP) stretch in the domain TV (alpha 1A(-NP)). Human alpha 1A channels carrying various polyglutamine length with or without NP were expressed in HEK293 cells, and channel properties were compared using a whole-cell voltage clamp technique. alpha 1A(-NP), corresponding to P-type channel, with 24 and 28 polyglutamines found in patients showed the voltage dependence of inactivation shifting negatively by 6 and 11 mV, respectively, from the 13 polyglutamine control. Contrarily, the alpha 1A channel with NP (alpha 1A(+NP)), corresponding to Q-type channel, with 28 polyglutamines exhibited a positive shift of 5 mV. These results suggest that altered function of alpha 1A(-NP) may contribute to degeneration of Purkinje cells, which express predominantly alpha 1A(-NP), due to the reduced Ca2+ influx resulting from the negative shift of voltage-dependent inactivation. On the other hand, other types of neurons, expressing both alpha 1A(-NP) and alpha 1A(+NP), may survive because the positive shift of voltage-dependent inactivation of alpha 1A(+NP) compensates Ca2+ influx.