Cdk5 regulates IP3R1-mediated Ca dynamics and Ca-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 transfer to the mitochondria, subsequently increasing mitochondrial Ca concentration ([Ca]). This suggests a role for Cdk5 in regulating intracellular Ca 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 Caconcentration ([Ca]), which is not due to reduced internal Ca store capacity or increased Ca influx from the extracellular milieu. Instead, by stimulation with ATP that mediates release of Ca from internal stores, we determined that the rise in [Ca] in Cdk5 MEFs is due to increased inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca release from internal stores. Cdk5 interacts with the IP3R1 Ca channel and phosphorylates it at Ser. Such phosphorylation controls IP3R1-mediated Ca release as loss of Cdk5, and thus, loss of IP3R1 Ser phosphorylation triggers an increase in IP3R1-mediated Ca release in Cdk5 MEFs, resulting in elevated [Ca]. Elevated [Ca] 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], 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 dynamics due to Cdk5 loss correspond to accelerated cell proliferation that correlates with increased body weight and size in Cdk5 embryos.