Inositol 1, 4, 5-trisphosphate receptor (IP 3 R)-mediated Ca 2+ release from the endoplasmic reticulum (ER) triggers many physiological responses in neurons, and when uncontrolled can cause ER stress that contributes to neurological disease. Here we show that the unfolded protein response (UPR) in neurons induces rapid translocation of nuclear receptor-interacting protein 140 (RIP140) to the cytoplasm. In the cytoplasm, RIP140 localizes to the ER by binding to the IP 3 R. The carboxyl-terminal RD4 domain of RIP140 interacts with the carboxyl-terminal gate-keeping domain of the IP 3 R. This molecular interaction disrupts the IP 3 Râ €™ s â €∼ head-tailâ €™ interaction, thereby suppressing channel opening and attenuating IP 3 R-mediated Ca 2+ release. This contributes to a rapid suppression of the ER stress response and provides protection from apoptosis in both hippocampal neurons in vitro and in an animal model of ER stress. Thus, RIP140 translocation to the cytoplasm is an early response to ER stress and provides protection against neuronal death.