Submitted on June 26, 2006
Accepted on October 2, 2006
Altered frequency-dependent inactivation and steady state inactivation of polyglutamine-expanded 
1A in SCA6
Haiyan Chen1 and Erika Piedras-Renteria2*
1 Physiology, Loyola University Chicago, MAywood, Illinois, United States
2 Physiology, Loyola University Chicago, Illinois, United States
* To whom correspondence should be addressed. E-mail: epiedra{at}lumc.edu.
SCA6 (Spinocerebellar ataxia type 6) 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 non-pathogenic size of 4 to 18 glutamines (CAG4-18) to CAG19-33 in SCA6. The molecular basis of SCA6 is poorly understood. To date, the biophysical properties studied in heterologous systems support both, a gain or a loss of channel function in SCA6.
Here, 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 carboxy-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 C-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.
