Faculty of Medicine and Health Sciences, Department of Pharmacology, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
J Cell Biochem. 2011 Feb;112(2):723-33. doi: 10.1002/jcb.23006.
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.
三磷酸肌醇受体（IP3R）是一种配体门控钙通道，是无兴奋细胞内钙动员的主要调节因子。越来越多的证据表明，细胞外信号通路的激活可以调节钙信号通路的特定调节控制。在本研究中，我们研究了 PI3-激酶/哺乳动物雷帕霉素靶蛋白（mTOR）通路对 RINm5F 细胞中 IP3R/Ca2+信号通路活性的影响。我们使用共免疫沉淀的方法表明，mTOR 以 mTOR 活性依赖的方式与 IP3R-3 发生物理相互作用。我们还表明，IP3R 在细胞内被 mTOR 磷酸化。所有已知调节 mTOR 活性的条件（IGF-1、wortmannin、rapamycin、PP242 和营养饥饿）均被证明可以调节 RINm5F 细胞中 carbachol 诱导的 Ca2+信号。最后，我们使用一种直接测量 IP3R 活性的测定方法，表明 mTOR 增加了 IP3R 的表观亲和力。鉴于 mTOR 控制细胞增殖和细胞稳态，而 Ca2+在这两个现象中起着关键作用，因此当细胞的营养状态需要时，mTOR 促进 IP3R 介导的 Ca2+释放。
