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First published online 3 June 2003
doi: 10.1242/jcs.00595

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Journal of Cell Science 116, 2967-2974 (2003)
doi: 10.1242/jcs.00595

Research Article

Molecular determinants of cysteine string protein modulation of N-type calcium channels

Linda C. Miller1,*, Leigh Anne Swayne1,*, Jason G. Kay1, Zhong-Ping Feng1,2, Scott E. Jarvis1, Gerald W. Zamponi1 and Janice E. A. Braun1,{ddagger}

1 Neuroscience Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, T2N 4N1, Canada
2 NeuroMed Technologies Inc., Suite 301, Don Rix Building, 2389 Health Sciences Mall, UBC, Vancouver, BC, V6T 1Z4, Canada

{ddagger} Author for correspondence (e-mail: braunj{at}ucalgary.ca)

Accepted 3 April 2003

Cysteine string proteins (CSPs) are secretory vesicle chaperones that are important for neurotransmitter release. We have previously reported an interaction of CSP with both heterotrimeric GTP-binding proteins (G proteins) and N-type calcium channels that results in a tonic G protein inhibition of the channels. In this report we directly demonstrate that two separate regions of CSP associate with G proteins. The N-terminal binding site of CSP, which includes the J domain, binds G{alpha} subunits but not G{alpha}ß subunits whereas the C terminal binding site of CSP associates with either free G{alpha}ß subunits or G{alpha}ß in complex with G{alpha}. The interaction of either binding site of CSP (CSP1-82 or CSP83-198) with G proteins elicits robust tonic inhibition of N-type calcium channel activity. However, CSP1-82 inhibition and CSP83-198 inhibition of calcium channels occur through distinct mechanisms. Calcium channel inhibition by CSP83-198 (but not CSP1-82) is completely blocked by co-expression of the synaptic protein interaction site (synprint) of the N-type channel, indicating that CSP83-198 inhibition is dependent on a physical interaction with the calcium channel. These results suggest that distinct binding sites of CSP can play a role in modulating G protein function and G protein inhibition of calcium channels.

Key words: Cysteine string protein, Chaperones, G proteins, N-type-calcium channels, Synaptic transmission, J domain




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