Cysteine String Protein (CSP) Inhibition of N-type Calcium Channels Is Blocked by Mutant Huntingtin
Date
2003
Authors
Miller, Linda C.
Swayne, Leigh Anne
Chen, Lina
Feng, Zhong-Ping
Wacker, Jennifer L.
Muchowski, Paul J.
Zamponi, Gerald W.
Braun, Janice E. A.
Journal Title
Journal ISSN
Volume Title
Publisher
The Journal of Biological Chemistry
Abstract
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.
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Citation
Miller, L.C., Swayne, L.A., Chen, L., Feng, Z-P., Wacker, J.L., Muchowski, P.J., … Braun, E.A. (2003). Cysteine string protein (CSP) inhibition of N-type calcium channels is blocked by mutant huntingtin. The Journal of Biological Chemistry, 278(52), 53072-53081.