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J. Biol. Chem., Vol. 278, Issue 52, 53072-53081, December 26, 2003

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Cysteine String Protein (CSP) Inhibition of N-type Calcium Channels Is Blocked by Mutant Huntingtin^*

Linda C. Miller, Leigh Anne Swayne, Lina Chen, Zhong-Ping Feng¶, Jennifer L. Wacker||, Paul J. Muchowski||**, Gerald W. Zamponi, and Janice E. A. Braun

From the Cellular and Molecular Neurobiology Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta T2N 4N1, Canada and the ^||Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280

Cysteine string protein (CSP), a 34-kDa molecular chaperone, is expressed on synaptic vesicles in neurons and on secretory vesicles in endocrine, neuroendocrine, and exocrine cells. CSP can be found in a complex with two other chaperones, the heat shock cognate protein Hsc70, and small glutamine-rich tetratricopeptide repeat domain protein (SGT). CSP function is vital in synaptic transmission; however, the precise nature of its role remains controversial. We have previously reported interactions of CSP with both heterotrimeric GTP-binding proteins (G proteins) and N-type calcium channels. These associations give rise to a tonic G protein inhibition of the channels. Here we have examined the effects of huntingtin fragments (exon 1) with (huntingtin^exon1/exp) and without (huntingtin^exon1/nonexp) expanded polyglutamine (polyQ) tracts on the CSP chaperone system. In vitro huntingtin^exon1/exp sequestered CSP and blocked the association of CSP with G proteins. In contrast, huntingtin^exon1/nonexp did not interact with CSP and did not alter the CSP/G protein association. Similarly, co-expression of huntingtin^exon1/exp with CSP and N-type calcium channels eliminated CSP's tonic G protein inhibition of the channels, while coexpression of huntingtin^exon1/nonexp did not alter the robust inhibition promoted by CSP. These results indicate that CSP's modulation of G protein inhibition of calcium channel activity is blocked in the presence of a huntingtin fragment with expanded polyglutamine tracts.

Received for publication, June 12, 2003 , and in revised form, October 20, 2003.

^* This work was supported by operating grants (to J. E. A. B. and G. W. Z.) from the Canadian Institutes of Health Research (CIHR) and an establishment grant (to J. E. A. B.) from the Alberta Foundation for Medical Research (AHFMR). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by Natural Science and Engineering Research Council, CIHR, and AHFMR studentships.

^¶ Recipient of postdoctoral fellowships from CIHR and Heart and Stroke Foundation of Canada.

^** Supported by the Hereditary Disease Foundation under the auspices of the Cure Huntington's Disease initiative.

An AHFMR senior scholar and a CIHR investigator.

Recipient of a New Investigator award from the CIHR and the Alberta Foundation for Medical Research. To whom correspondence should be addressed: Dept. of Physiology and Biophysics, Cellular and Molecular Neurobiology, University of Calgary, Calgary, Alberta T2N 4N1, Canada. Tel.: 403-220-5463; Fax: 403-283-8731; E-mail: braunj{at}ucalgary.ca.

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