Cysteine string protein (CSP alpha) is a member of the cellular folding machinery that is located on regulated secretory vesicles. We have previously shown that CSP alpha 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 G alpha s. Association of this CSPCE 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 CSP alpha/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 CSP alpha, Hsc70 as well as the synaptic protein interaction (synprint) region of N-type channels. We demonstrate that huntingtin(exon1), a putative biologically active fragment of huntingtin, displaces both syntaxin I A and CSP alpha from N-type channels. Identification of the protein components of the CSP alpha/GEF system is essential in establishing its precise role in synaptic transmission. (c) 2006 Elsevier Inc. All rights reserved.