Mammalian target of rapamycin (mTOR) phosphorylates inositol 1,4,5-trisphosphate receptor type 2 and increases its Ca2+ release activity

There is substantial evidence that crosstalk between the proliferation and Ca2+-signaling pathways plays a critical role in the regulation of normal physiological functions as well as in the pathogenesis of a variety of abnormal processes. In non-excitable cells, intracellular Ca2+ is mobilized through inositol 1,4,5-trisphosphate sensitive Ca2+ channels (IP3R) expressed on the endoplasmic reticulum. Here we report that mTOR, a point of convergence for signals from mitogenic growth factors, nutrients and cellular energy levels, phosphorylates the IP3R-2, the predominant isoform of IP3R in AR4-2J cells. Pretreatment with the mTOR inhibitor rapamycin, decreased carbachol-induced Ca2+ release in AR4-2J cells. Rapamycin also decreased IP3-induced Ca2+ release in permeabilized AR4-2J cells. We also showed that IGF-1 potentiates carbachol-induced Ca2+ release in AR4-2J cells, an effect that was prevented by rapamycin. Rapamycin also decreased carbachol-induced Ca2+ release in HEK 293A cells in which IP3R-1 and IP3R-3 had been knocked down. These results suggest that mTOR potentiates the activity of IP3R-2 by a phosphorylation mechanism. This conclusion supports the concept of crosstalk between Ca2+ signaling and proliferation pathways and thus provides another way by which intracellular Ca2+ signals are finely encoded.