Altered frequency-dependent inactivation and steady-state inactivation of polyglutamine-expanded alpha1A in SCA6

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease of the cerebellum and inferior olives characterized by a late-onset cerebellar ataxia and selective loss of Purkinje neurons (15, 16). SCA6 arises from an expansion of the polyglutamine tract located in exon 47 of the _1A (P/Q-type calcium channel) gene from a nonpathogenic size of 4 to 18 glutamines (CAG_4–18) to CAG_19–33 in SCA6. The molecular basis of SCA6 is poorly understood. To date, the biophysical properties studied in heterologous systems support both a gain and a loss of channel function in SCA6. We studied the behavior of the human _1A isoform, previously found to elicit a gain of function in disease (41), focusing on properties in which the COOH terminus of the channel is critical for function: we analyzed the current properties in the presence of ₄- and _2a-subunits (both known to interact with the _1A COOH terminus), current kinetics of activation and inactivation, calcium-dependent inactivation and facilitation, voltage-dependent inactivation, frequency dependence, and steady-state activation and inactivation properties. We found that SCA6 channels have decreased activity-dependent inactivation and a depolarizing shift (+6 mV) in steady-state inactivation properties consistent with a gain of function. trinucleotide repeats; ataxia; calmodulin