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Department of Pharmacology, Faculty of Medicine and Health Sciences, University of Sherbrooke, 3001 12th Avenue North, Sherbrooke, Quebec, Canada J1H 5N4

(Requests for offprints should be addressed to G Guillemette; Email: gaetan.guillemette{at}usherbrooke.ca)

In non-excitable cells, the inositol 1,4,5-trisphosphate receptor channel, which plays a major (IP₃R) is an intracellular Ca²⁺ role in Ca²⁺ signalling. Three isoforms of IP₃R have been identified (IP₃R-1, IP₃R-2 and IP₃R-3) and most cell types express different proportions of each isoform. The differences between the pharmacological and functional properties of the various isoforms of IP₃R are poorly understood. AR4-2J cells, which express almost exclusively (~86%) the IP₃R-2, represent an interesting model to study this particular isoform. Here, we investigated a regulatory mechanism by which protein kinase C (PKC) influences IP₃R-2-mediated Ca²⁺ release. Using an immunoprecipitation approach, we confirmed that AR4-2J cells express almost exclusively the IP₃R-2 isoform. Using an in vitro phosphorylation assay, we showed that the immunopurified IP₃R-2 was efficiently phosphorylated by exogenous PKC. In intact AR4-2J cells metabolically labelled with ³²Pi, we showed that phorbol-12-myristate-13-acetate (PMA) and Ca²⁺ mobilizing agonists cause the phosphorylation of IP₃R-2. In saponin-permeabilized AR4-2J cells, IP₃-induced Ca²⁺ release was reduced after a pre-treatment with PMA or with exogenous PKC. PMA also reduced the Ca²⁺ response of intact AR4-2J cells stimulated with carbachol and epidermal growth factor, two agonists that use different receptor types to activate phospholipase C. These results demonstrate that PKC decreases the Ca²⁺mobilizing activity of IP₃R-2 and thus exerts a negative feedback on the agonists-induced Ca²⁺ response of AR4-2J cells.

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