The cysteine string protein multimeric complex

Cysteine string protein (CSPα) is a member of the cellular folding machinery that is located on regulated secretory vesicles. We have previously shown that CSPα in association with Hsc70 (70 kDa heat shock cognate protein) and SGT (small glutamine-rich tetratricopeptide repeat domain protein) is a guanine nucleotide exchange factor (GEF) for Gαs. Association of this CSPα complex with N-type calcium channels, a channel key in coupling calcium influx with synaptic vesicle exocytosis, triggers tonic G protein inhibition of the channels. Syntaxin 1A, a plasma membrane SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) critical for neurotransmission, coimmunoprecipitates with the CSPα/G protein/N-type calcium channel complex, however the significance of syntaxin 1A as a component of this complex remains unknown. In this report, we establish that syntaxin 1A interacts with CSPα, Hsc70 as well as the synaptic protein interaction (synprint) region of N-type channels. We demonstrate that huntingtinexon1, a putative biologically active fragment of huntingtin, displaces both syntaxin 1A and CSPα from N-type channels. Identification of the protein components of the CSPα/GEF system is essential in establishing its precise role in synaptic transmission.