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 Ca2+ transfer to the mitochondria, subsequently increasing mitochondrial Ca2+ concentration ([Ca2+](mt)). This suggests a role for Cdk5 in regulating intracellular Ca2+ 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 ([Ca2+](cyt)), which is not due to reduced internal Ca2+ store capacity or increased Ca2+ influx from the extracellular milieu. Instead, by stimulation with ATP that mediates release of Ca2+ from internal stores, we determined that the rise in [Ca2+](cyt) in Cdk5(-/-) MEFs is due to increased inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ release from internal stores. Cdk5 interacts with the IP3R1 Ca2+ channel and phosphorylates it at Ser(421). Such phosphorylation controls IP3R1-mediated Ca2+ release as loss of Cdk5, and thus, loss of IP3R1 Ser(421) phosphorylation triggers an increase in IP3R1-mediated Ca2+ release in Cdk5(-/-) MEFs, resulting in elevated [Ca2+](cyt). Elevated [Ca2+](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 [Ca2+](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 Ca2+ dynamics due to Cdk5 loss correspond to accelerated cell proliferation that correlates with increased body weight and size in Cdk5(-/-) embryos.

Automated summary

Loss of Cdk5 causes an increase in cytosolic calcium concentration, promoting cell proliferation and increased body weight in embryos. Cdk5 interacts with IP3R1 and regulates IP3R1-mediated calcium release through phosphorylation.