Regulation of chemoattractant receptors of the formyl peptide receptor family

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Formyl peptide receptors (FPRs) are a family of G protein-coupled receptors primarily expressed on granulocytes and monocytes. They guide leukocytes towards sites of bacterial infections by sensing gradients of chemotactic bacterial peptides of the prototype formyl-Met-Leu-Phe (fMLF). Recent evidence shows that FPRs can also interact with a number of ligands of non-bacterial origin. Among these we could identify the anti-inflammatory protein annexin 1 as an endogenous FPR ligand. Annexin 1, which is most likely released from cells at sites of inflammation, can desensitize FPRs thereby blocking leukocyte extravasation along fMLF gradients. Based on these observations we now want to characterize the mechanistic basis of the annexin 1-mediated FPR regulation. First, intracellular signalling following FPR activation by the endogenous ligand annexin 1 should be analyzed and compared to that initiated by fMLF. Moreover, we want to characterize the intracellular itinerary of FPR in response to agonist (annexin 1/fMLF)-induced endocytosis. Second, the annexin 1 binding site in the receptor should be identified. Third, recently identified genes acting downstream of annexin 1-activated FPR should be characterized functionally with respect to their role in monocyte transendothelial migration.