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Activation of Subunits of G_i2 and G_i3 Proteins by Basic Secretagogues Induces Exocytosis Through Phospholipase C and Arachidonate Release Through Phospholipase C in Mast Cells

Laboratoire de Neuroimmunopharmacologie, Institut National de la Santé et de la Recherche Médicale, Unité 425, Université Louis Pasteur-Strasbourg I, Faculté de Pharmacie, Illkirch, France

Mast cells are activated by Ag-induced clustering of IgE bound to FcRI receptors or by basic secretagogues that stimulate pertussis toxin-sensitive heterotrimeric G proteins. The cell response includes the secretion of stored molecules, such as histamine, through exocytosis and of de novo synthesized mediators, such as arachidonate metabolites. The respective roles of G proteins and subunits as well as various types of phospholipase C (PLC) in the signaling pathways elicited by basic secretagogues remain unknown. We show that a specific Ab produced against the C-terminus of G_i3 and an anti-recombinant G_i2 Ab inhibited, with additive effects, both exocytosis and arachidonate release from permeabilized rat peritoneal mast cells elicited by the basic secretagogues mastoparan and spermine. A specific Ab directed against G dimers prevented both secretions. Anti-PLC Abs selectively prevented exocytosis. The selective phosphatidylinositol 3-kinase inhibitor LY 294002 prevented arachidonate release without modifying exocytosis. G coimmunoprecipitated with PLC and phosphatidylinositol 3-kinase. The anti-PLC1 and anti-phospholipase A₂ Abs selectively blocked arachidonate release. Protein tyrosine phosphorylation was inhibited by anti-G Abs, LY294002, and anti PLC1 Abs. These data show that the early step of basic secretagogue transduction is common to both signaling pathways, involving subunits of G_i2 and G_i3 proteins. Activated G interacts, on one hand, with PLC to elicit exocytosis and, on the other hand, with phosphatidylinositol 3-kinase to initiate the sequential activation of PLC1, tyrosine kinases, and phospholipase A₂, leading to arachidonate release.

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