Functional selective ATP receptor signaling controlled by the free fatty acid receptor 2 through a novel allosteric modulation mechanism

Abstract

A nonactivating allosteric modulator of free fatty acid receptor 2 (FFA2R, also called GPCR 43) turns both propionate (an orthosteric FFA2R agonist) and ATP (an agonist for the purinergic P2Y2 receptor), into potent activating ligands that trigger an assembly of the superoxide-generating neutrophil NADPH oxidase. The ATP-induced activation requires the participation of FFA2R, and the signaling is biased toward oxidase activation, leaving the ATP-induced rise in intracellular Ca2+ unaffected. No NADPH oxidase activity was induced by ATP when propionate replaced the allosteric modulator. Signaling downstream of propionate-activated FFA2Rs was insensitive to Gαq inhibition, but the crosstalk activation involving both FFA2R and P2Y2R relied on Gαq signaling. The receptor crosstalk, by which allosterically modulated FFA2Rs communicate with P2Y2Rs and generate NADPH oxidase activating signals downstream of Gαq, represent a novel mechanism by which GPCR activities can be regulated from inside the plasma membrane. Further, the finding that an allosteric FFA2R modulator sensitizes not only the response induced by orthosteric FFA2R agonists, but also the response induced by ATP (P2Y2R-specific agonist) and formyl peptide receptor-specific agonists, violates the receptor restriction characteristics normally defining the selectivity of allosteric GPCR modulators.-Lind, S., Holdfeldt, A., Mårtensson, J., Sundqvist, M., Björkman, L., Forsman, H., Dahlgren, C. Functional selective ATP receptor signaling controlled by the free fatty acid receptor 2 through a novel allosteric modulation mechanism.