G(i)-mediated activation of the Syk kinase by the receptor mimetic basic secretagogues of mast cells: Role in mediating arachidonic acid/metabolites release

Syk kinase is essential for Fc epsilon RI-mediated signaling and release of inflammatory mediators from mast cells. We now show that activation of rat peritoneal mast cells by the nonimmunological, Gi-mediated pathway also re sults in the activation of Syk. We show that compound 48/80 (c48/80), a rec eptor analogue that activates directly G proteins, activates Syk in a pertu ssis toxin-sensitive fashion. We further show that Syk activation by c48/80 is blocked by the protein kinase C inhibitor GF109203X, by the phosphatidy linositol 3-kinase inhibitors, wortmannin and LY294002, by EGTA, and by the selective src-like kinase inhibitor PP1. These results suggest that in the nonimmunological, Gi-mediated pathway, Syk is located downstream from phos pholipase C and phosphatidylinositol 3-kinase. However, in common with the Fc epsilon RI-mediated pathway, activation of Syk by c48/80 is dependent on a src-like protein tyrosine kinase. Finally, we show that in the nonimmuno logical pathway, Syk plays a central role in the release of arachidonic aci d/eicosanoid metabolites, but not in the release of prestored mediators suc h as histamine. The Journal of Immunology, 2001.