title: Altered frequency-dependent inactivation and steady-state inactivation of polyglutamine-expanded alpha1A in SCA6.
abstract: 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. 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 (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 alpha(1A) isoform, previously found to elicit a gain of function in disease, focusing on properties in which the COOH terminus of the channel is critical for function: we analyzed the current properties in the presence of beta(4)- and beta(2a)-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.
authors.affiliation: Dept. of Physiology, Loyola Univresity Chicago, Maywood, IL 60153-5500, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chen
authors.forename: Erika S
authors.initials: ES
authors.lastname: Piedras-Rentería
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology*; D002147:Calmodulin / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D007668:Kidney; D017774:Long-Term Potentiation / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology; D010455:Peptides / Q000378:metabolism*; D020864:Calcium Channels, N-Type
chemical_list: D002118:Calcium; D015220:Calcium Channels; D002147:Calmodulin; D010455:Peptides; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type; C097188:polyglutamine