Cysteine string protein alpha (CSP alpha) is a regulated vesicle protein and molecular chaperone that has been found to be critical for continuous synaptic transmission and is implicated in the defense against neurodegeneration. Previous work has revealed links between CSP alpha and heterotrimeric GTP binding protein (G protein) signal transduction pathways. We have shown that CSP alpha is a guanine nucleotide exchange factor (GEF) for G(alpha s). In vitro Hsc70 (70 kDa heat shock cognate protein) and SGT (small glutamine-rich tetratricopeptide repeat domain protein) switch CSP alpha from an inactive GEF to an active GEF. Here we have examined the cellular distribution of the CSP alpha system in the PC12 neuroendocrine cell line. CSP alpha, an established secretory vesicle protein, was found to concentrate in the processes of NGF-differentiated PC12 cells as expected. G(beta) subunits co-localized and G(alpha s) subunits partially co-localized with CSP alpha. However, under the conditions examined, the GEF activity of CSP alpha is expected to be inactive, in that Hsc70 was not found in PC12 processes. These results indicate that CSP alpha activity is subject to regulation by factors that alter Hsc70 distribution and translocation within the cell. (c) 2006 Elsevier Inc. All rights reserved.