Cdk5 regulates IP3R1-mediated Ca(2+) dynamics and Ca(2+)-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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04515-8.