Journal
HUMAN MOLECULAR GENETICS
Volume 15, Issue 10, Pages 1587-1599Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddl080
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Funding
- NCI NIH HHS [P30 CA77598] Funding Source: Medline
- NINDS NIH HHS [NS38332] Funding Source: Medline
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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 beta 3 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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