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Am J Physiol Cell Physiol 292: C1078-C1086, 2007. First published October 4, 2006; doi:10.1152/ajpcell.00353.2006
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NERVOUS SYSTEM CELL BIOLOGY

Altered frequency-dependent inactivation and steady-state inactivation of polyglutamine-expanded {alpha}1A in SCA6

Haiyan Chen and Erika S. Piedras-Rentería

Department of Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois

Submitted 26 June 2006 ; accepted in final form 2 October 2006

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 {alpha}1A (P/Q-type calcium channel) gene from a nonpathogenic 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 and a loss of channel function in SCA6. We studied the behavior of the human {alpha}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 beta4- and beta2a-subunits (both known to interact with the {alpha}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


Address for reprint requests and other correspondence: E. S. Piedras-Rentería, Dept. of Physiology, Loyola Univ. Chicago, 2160 South First Ave., Maywood, IL 60153-5500 (e-mail: epiedra{at}lumc.edu)






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