Positive regulation of inositol 1,4,5‐trisphosphate‐induced ca 2+ release by mammalian target of rapamycin (mTOR) in RINm5F cells

The inositol 1,4,5‐trisphosphate receptor (IP 3 R), a ligand‐gated Ca 2+ channel, is the main regulator of intracellular Ca 2+ mobilization in non‐excitable cells. An emerging body of evidence suggests that specific regulatory control of the Ca 2+ signaling pathway is modulated by the activation of additional signaling pathways. In the present study, we investigated the influence of the PI3‐kinase/mammalian target of rapamycin (mTOR) pathway on the activity of the IP 3 R/Ca 2+ signaling pathway in RINm5F cells. We used a co‐immunoprecipitation approach to show that mTOR physically interacts with IP 3 R‐3 in an mTOR activity‐dependent manner. We also showed that IP 3 R is phosphorylated by mTOR in cellulo. All the conditions known to modulate mTOR activity (IGF‐1, wortmannin, rapamycin, PP242, and nutrient starvation) were shown to modify carbachol‐induced Ca 2+ signaling in RINm5F cells. Lastly, we used an assay that directly measures the activity of IP 3 R, to show that mTOR increases the apparent affinity of IP 3 R. Given that mTOR controls cell proliferation and cell homeostasis, and that Ca 2+ plays a key role in these two phenomena, it follows that mTOR facilitates IP 3 R‐mediated Ca 2+ release when the nutritional status of cells requires it. J. Cell. Biochem. 112: 723–733, 2011. © 2011 Wiley‐Liss, Inc.