Skip Navigation



Human Molecular Genetics Advance Access published online on April 4, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl080
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
15/10/1587    most recent
ddl080v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Kordasiewicz, H. B.
Right arrow Articles by Gomez, C. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kordasiewicz, H. B.
Right arrow Articles by Gomez, C. M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2006. Published by Oxford University Press. All rights reserved
Received November 12, 2005
Revised March 24, 2006
Accepted March 24, 2006

Article

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

Holly B. Kordasiewicz 1, Randall M. Thompson 1, H. Brent Clark 2, and Christopher M. Gomez 3 *

1 Departments of Neuroscience and Neurology, University of Minnesota, Minneapolis, Minnesota 55455, USA
2 Section of Neuropathologym, University of Minnesota, Minneapolis, Minnesota 55455, USA
3 Departments of Neuroscience and Neurology, University of Minnesota, 420 Delaware Street S.E., Minneapolis, Minnesota 55455, USA

* To whom correspondence should be addressed.
Christopher M. Gomez, E-mail: gomez001{at}umn.edu


  Abstract

P/Q-type voltage-gated calcium channels are regulated, in part, through the cytoplasmic carboxyl terminus (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 kD 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. HEK cells stably expressing {beta}3 and {alpha}2{delta} subunits and transiently transfected with full-length human {alpha}1A contain a 75 kD CT-2 reactive peptide in their nuclear fraction. Primary granule cells transfected with C-terminally 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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Arch NeurolHome page
V. G. Shakkottai and H. L. Paulson
Physiologic Alterations in Ataxia: Channeling Changes Into Novel Therapies
Arch Neurol, October 1, 2009; 66(10): 1196 - 1201.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
E. Schroder, M. Byse, and J. Satin
L-Type Calcium Channel C Terminus Autoregulates Transcription
Circ. Res., June 19, 2009; 104(12): 1373 - 1381.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
K. Watase, C. F. Barrett, T. Miyazaki, T. Ishiguro, K. Ishikawa, Y. Hu, T. Unno, Y. Sun, S. Kasai, M. Watanabe, et al.
Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant CaV2.1 channels
PNAS, August 19, 2008; 105(33): 11987 - 11992.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
B. Mellstrom, M. Savignac, R. Gomez-Villafuertes, and J. R. Naranjo
Ca2+-Operated Transcriptional Networks: Molecular Mechanisms and In Vivo Models
Physiol Rev, April 1, 2008; 88(2): 421 - 449.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. V. Todi, M. N. Laco, B. J. Winborn, S. M. Travis, H. M. Wen, and H. L. Paulson
Cellular Turnover of the Polyglutamine Disease Protein Ataxin-3 Is Regulated by Its Catalytic Activity
J. Biol. Chem., October 5, 2007; 282(40): 29348 - 29358.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Cell Physiol.Home page
H. Chen and E. S. Piedras-Renteria
Altered frequency-dependent inactivation and steady-state inactivation of polyglutamine-expanded {alpha}1A in SCA6
Am J Physiol Cell Physiol, March 1, 2007; 292(3): C1078 - C1086.
[Abstract] [Full Text] [PDF]

Home page
 Sci SignalHome page
J. R. Naranjo and B. Mellstrom
Split Personality of Transcription Factors Inside and Outside the Nuclear Border
Sci. Signal., January 30, 2007; 2007(371): pe5 - pe5.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
B. E. Riley and H. T Orr
Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle.
Genes & Dev., August 15, 2006; 20(16): 2183 - 2192.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.