Cdk5 regulates IP3R1-mediated Ca2+ dynamics and Ca2+-mediated cell proliferation

Loss of cyclin-dependent kinase 5 (Cdk5) in the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) increases ER–mitochondria tethering and ER Ca 2+ transfer to the mitochondria, subsequently increasing mitochondrial Ca 2+ concentration ([Ca 2+ ] mt ). This suggests a role for Cdk5 in regulating intracellular Ca 2+ dynamics, but how Cdk5 is involved in this process remains to be explored. Using ex vivo primary mouse embryonic fibroblasts (MEFs) isolated from Cdk5 −/− mouse embryos, we show here that loss of Cdk5 causes an increase in cytosolic Ca 2+ concentration ([Ca 2+ ] cyt ), which is not due to reduced internal Ca 2+ store capacity or increased Ca 2+ influx from the extracellular milieu. Instead, by stimulation with ATP that mediates release of Ca 2+ from internal stores, we determined that the rise in [Ca 2+ ] cyt in Cdk5 −/− MEFs is due to increased inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca 2+ release from internal stores. Cdk5 interacts with the IP3R1 Ca 2+ channel and phosphorylates it at Ser 421 . Such phosphorylation controls IP3R1-mediated Ca 2+ release as loss of Cdk5, and thus, loss of IP3R1 Ser 421 phosphorylation triggers an increase in IP3R1-mediated Ca 2+ release in Cdk5 −/− MEFs, resulting in elevated [Ca 2+ ] cyt . Elevated [Ca 2+ ] cyt in these cells further induces the production of reactive oxygen species (ROS), which upregulates the levels of Nrf2 and its targets, Prx1 and Prx2. Cdk5 −/− MEFs, which have elevated [Ca 2+ ] cyt , proliferate at a faster rate compared to wt, and Cdk5 −/− embryos have increased body weight and size compared to their wt littermates. Taken together, we show that altered IP3R1-mediated Ca 2+ dynamics due to Cdk5 loss correspond to accelerated cell proliferation that correlates with increased body weight and size in Cdk5 −/− embryos.