Positive Regulation of Inositol 1,4,5-Trisphosphate-Induced Ca2+ Release by Mammalian Target of Rapamycin (mTOR) in RINm5F Cells

The inositol 1,4,5-trisphosphate receptor (IP3R), a ligand-gated Ca2+ channel, is the main regulator of intracellular Ca2+ mobilization in non-excitable cells. An emerging body of evidence suggests that specific regulatory control of the Ca2+ 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 IP3R/Ca2+ signaling pathway in RINm5F cells. We used a co-immunoprecipitation approach to show that mTOR physically interacts with IP3R-3 in an mTOR activity-dependent manner. We also showed that IP3R 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 Ca2+ signaling in RINm5F cells. Lastly, we used an assay that directly measures the activity of IP3R, to show that mTOR increases the apparent affinity of IP3R. Given that mTOR controls cell proliferation and cell homeostasis, and that Ca2+ plays a key role in these two phenomena, it follows that mTOR facilitates IP3R-mediated Ca2+ release when the nutritional status of cells requires it. J. Cell. Biochem. 112: 723-733, 2011. (C) 2010 Wiley-Liss, Inc.