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Human Molecular Genetics Advance Access originally published online on April 4, 2006
Human Molecular Genetics 2006 15(10):1587-1599; doi:10.1093/hmg/ddl080
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

C-termini of P/Q-type Ca2+ channel {alpha}1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity

Holly B. Kordasiewicz1,2, Randall M. Thompson1,2, H. Brent Clark2,3 and Christopher M. Gomez1,2,*

1Department of Neuroscience, 2Department of Neurology and 3Section of Neuropathology, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA

* To whom correspondence should be addressed at: Department of Neurology, AMB S237, MC2030, The University of Chicago, 5841 S. Maryland, Chicago, IL 60637, USA. Tel: +1 7737026390; Fax: +1 7737025670; Email: gomez001{at}uchicago.edu

Received November 12, 2005; Accepted March 24, 2006

P/Q-type voltage-gated calcium channels are regulated, in part, through the cytoplasmic C-terminus of their {alpha}1A subunit. Genetic absence or alteration of the C-terminus leads to abnormal channel function and neurological disease. Here, we show that the terminal 60–75 kDa of the endogenous {alpha}1A C-terminus is cleaved from the full-length protein and is present in cell nuclei. Antiserum to the C-terminus (CT-2) labels both wild-type mouse and human Purkinje cell nuclei, but not leaner mouse cerebellum. Human embryonic kidney cells stably expressing ß3 and {alpha}2{delta} subunits and transiently transfected with full-length human {alpha}1A contain a 75 kDa CT-2 reactive peptide in their nuclear fraction. Primary granule cells transfected with C-terminally Green fluorescent protein (GFP)-tagged {alpha}1A exhibit GFP nuclear labeling. Nuclear translocation depends partly on the presence of three nuclear localization signals within the C-terminus. The C-terminal fragment bears a polyglutamine tract which, when expanded (Q33) as in spinocerebellar ataxia type 6 (SCA6), is toxic to cells. Moreover, polyglutamine-mediated toxicity is dependent on nuclear localization. Finally, in the absence of flanking sequence, the Q33 expansion alone does not kill cells. These results suggest a novel processing of the P/Q-type calcium channel and a potential mechanism for the pathogenesis of SCA6.


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