Journal Article

C-termini of P/Q-type Ca<sup>2+</sup> channel α1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity

Holly B. Kordasiewicz, Randall M. Thompson, H. Brent Clark and Christopher M. Gomez

in Human Molecular Genetics

Volume 15, issue 10, pages 1587-1599
Published in print May 2006 | ISSN: 0964-6906
Published online April 2006 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddl080
C-termini of P/Q-type Ca2+ channel α1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity

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P/Q-type voltage-gated calcium channels are regulated, in part, through the cytoplasmic C-terminus of their α1A 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 α1A 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 β3 and α2δ subunits and transiently transfected with full-length human α1A contain a 75 kDa CT-2 reactive peptide in their nuclear fraction. Primary granule cells transfected with C-terminally Green fluorescent protein (GFP)-tagged α1A 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.

Journal Article.  9192 words.  Illustrated.

Subjects: Genetics and Genomics

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