Reactivation of Gi-coupled formyl peptide receptors is inhibited by Gq-selective inhibitors when induced by signals generated by the platelet-activating factor receptor

Formyl peptide receptor (FPR)-desensitized neutrophils display increased production/release of superoxide (O-2(-)) when activated by platelet-activating factor (PAF), a priming of the response achieved through a unique receptor crosstalk mechanism. The aim of this study was to determine the effect of an inhibitor selective for small, heterotrimeric G proteins belonging to the Gq subclass on that receptor crosstalk. We show that signals generated by FPRs and the PAF receptor (PAFR) induce activation of the neutrophil O-2(-), producing NADPH-oxidase, and that response was sensitive to Gq inhibition in cells activated by PAF, but no inhibition was obtained in cells activated by FPR agonists. Signaling in naive neutrophils is terminated fairly rapidly, and the receptors become homologously desensitized. The downstream sensitivity to Gq inhibition in desensitized cells displaying increased production/release of O-2(-) through the PAFR receptor crosstalk mechanism also comprised the reactivation of the FPRs, and the activation signals were redirected from the PAFR to the desensitized/reactivated FPRs. The Gq-dependent activation signals generated by the PAFRs activate the Gi-coupled FPRs, a receptor crosstalk that represents a novel pathway by which G protein-coupled receptors can be regulated and signaling can be turned on and off.