RACK1 binds to inositol 1,4,5-trisphosphate receptors and mediates Ca ²⁺ release

RACK1 is not a G protein but closely resembles the heterotrimeric Gβ-subunit. RACK1 serves as a scaffold, linking protein kinase C to its substrates. We demonstrate that RACK1 physiologically binds inositol 1,4,5-trisphosphate receptors and regulates Ca²⁺ release by enhancing inositol 1,4,5-trisphosphate receptor binding affinity for inositol 1,4,5-trisphosphate. Overexpression of RACK1 or depletion of RACK1 by interference RNA markedly augments or diminishes Ca²⁺ release, respectively, without affecting Ca²⁺ entry. These findings establish RACK1 as a physiologic mediator of agonist-induced Ca²⁺ release.