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Insulin Promotes the Association of Heat Shock Protein 90 with the Inositol 1,4,5-Trisphosphate Receptor to Dampen Its Ca²⁺ Release Activity

Department of Pharmacology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4

Address all correspondence and requests for reprints to: Guylain Boulay, Department of Pharmacology, Faculty of Medicine and Health Sciences, University of Sherbrooke, 3001 12th Avenue North, Sherbrooke, Québec, Canada J1H 5N4. E-mail: guylain.boulay{at}usherbrooke.ca.

The inositol 1,4,5-trisphosphate receptor (IP₃R) is a Ca²⁺ release channel that plays a pivotal role in regulating intracellular Ca²⁺ levels in resting cells. Three isoforms of IP₃Rs have been identified, and they all possess a large regulatory domain that covers about 60% of the protein. This regulation is accomplished by interaction with small molecules, posttranslational modifications, and mostly protein-protein interactions. In our search for new binding partners of the IP₃R, we found that 90-kDa heat-shock protein (Hsp90) binds to the IP₃R. This interaction increased on stimulation of HEK293T6.11 cells with insulin but not with G_q protein-coupled receptor (G_qPCR) agonists. Moreover, the Hsp90 inhibitor geldanamycin (GA) disrupted the interaction between Hsp90 and the IP₃R. Pretreatment of HEK293T6.11 cells with GA greatly increased the intracellular Ca²⁺ release induced by a G_qPCR agonist. Insulin alone did not induce any intracellular Ca²⁺ release. However, insulin diminished the intracellular Ca²⁺ release induced by a G_qPCR agonist. Interestingly, GA abolished the inhibitory effect of insulin on G_qPCR-induced intracellular Ca²⁺ release. Furthermore, in our search for a mechanistic explanation to this phenomenon, we found that inhibition of kinases activated downstream of the insulin receptor greatly increased the interaction between Hsp90 and the IP₃R. Of greater interest, we found that the simultaneous inhibition of mammalian target of rapamycin and the Src kinase almost completely disrupted the interaction between Hsp90 and the IP₃R. These results demonstrate that insulin promotes the interaction of Hsp90 with the IP₃R to dampen its Ca²⁺ release activity by a complex mechanism involving mammalian target of rapamycin and the Src kinase.