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

Abnormal CAG repeat expansion in the alpha 1A voltage-dependent calcium cha nnel gene is associated with spinocerebellar ataxia type 6, an autosomal do minant cerebellar ataxia with a predominant loss of the Purkinje cell. A re verse transcriptase-polymerase chain reaction analysis of mRNA from mouse P urkinje cells revealed a predominant expression of the alpha 1A channel lac king an asparagine-proline (NP) stretch in the domain TV (alpha 1A(-NP)). H uman alpha 1A channels carrying various polyglutamine length with or withou t NP were expressed in HEK293 cells, and channel properties were compared u sing 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, resp ectively, from the 13 polyglutamine control. Contrarily, the alpha 1A chann el with NP (alpha 1A(+NP)), corresponding to Q-type channel, with 28 polygl utamines exhibited a positive shift of 5 mV. These results suggest that alt ered function of alpha 1A(-NP) may contribute to degeneration of Purkinje c ells, which express predominantly alpha 1A(-NP), due to the reduced Ca2+ in flux resulting from the negative shift of voltage-dependent inactivation. O n 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.