Editors' ChoiceCALCIUM REGULATION

RACK1-Promoted Calcium Release

Science's STKE  02 Mar 2004:
Vol. 2004, Issue 222, pp. tw77-TW77
DOI: 10.1126/stke.2222004TW77

The protein RACK1 (receptor for activated C kinase 1) binds active forms of protein kinase C (PKC) and is thought to function as a scaffold or adaptor protein in various signaling pathways. Patterson et al. discovered a new role for RACK1 when it showed up in a two-hybrid screen for proteins interacting with fragments of the inositol 1,4,5-trisphosphate receptor (IP3R). The authors went on to show the interaction of the full-length endogenous proteins in vivo in PC12 cells. Furthermore, RACK1 appeared to increase the affinity of IP3 for the IP3R in preparations of membranes from rat brain or in microsomal membranes from COS7 cells. In multiple cell types from various species, depletion of RACK1 with siRNA reduced Ca2+ release in response to agonists (including uridine triphosphate, carbachol, and vasopressin) that normally stimulate IP3-dependent Ca2+ release from intracellular stores. Though the IP3R is thought to be a substrate for PKC, pharmacological inhibition of PKC did not affect basal or RACK1-stimulated Ca2+ release in response to activation of purinergic receptors in PC12 cells. RACK1 has been implicated in neuronal physiology and pathology, and modulation of Ca2+ release through IP3Rs will now need to be considered along with other potential mechanisms of RACK1 action.

R. L. Patterson, D. B. van Rossum, R. K. Barrow, S. H. Snyder, RACK1 binds to inositol 1,4,5-trisphosphate receptors and mediates Ca2+ release. Proc. Natl. Acad. Sci. U.S.A. 101, 2328-2332 (2004). [Abstract] [Full Text]