Mammalian target of rapamycin (mTOR) phosphorylates inositol 1,4,5-trisphosphate receptor type 2 and increases its Ca(2+) release activity.
There is substantial evidence that crosstalk between the proliferation and Ca(2+)-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 Ca(2+) is mobilized through inositol 1,4,5-trisphosphate sensitive Ca(2+) channels (IP(3)R) 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 IP(3)R-2, the predominant isoform of IP(3)R in AR4-2J cells. Pretreatment with the mTOR inhibitor rapamycin, decreased carbachol-induced Ca(2+) release in AR4-2J cells. Rapamycin also decreased IP(3)-induced Ca(2+) release in permeabilized AR4-2J cells. We also showed that IGF-1 potentiates carbachol-induced Ca(2+) release in AR4-2J cells, an effect that was prevented by rapamycin. Rapamycin also decreased carbachol-induced Ca(2+) release in HEK 293A cells in which IP(3)R-1 and IP(3)R-3 had been knocked down. These results suggest that mTOR potentiates the activity of IP(3)R-2 by a phosphorylation mechanism. This conclusion supports the concept of crosstalk between Ca(2+) signaling and proliferation pathways and thus provides another way by which intracellular Ca(2+) signals are finely encoded.
Régimbald-Dumas
Yannik
Y
Department of Pharmacology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Québec, Canada.
Frégeau
Marc-Olivier
MO
Guillemette
Gaétan
G
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D034741:RNA, Small Interfering; D007334:Insulin-Like Growth Factor I; D002217:Carbachol; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D002118:Calcium; D020123:Sirolimus