GRK5 regulates endocytosis of FPR2 independent of β-Arrestins.

The formyl-peptide receptor 2 (FPR2) is a G-protein-coupled receptor (GPCR) that responds to pathogen-derived peptides and regulates both pro-inflammatory and pro-resolution cellular processes. While ligand selectivity and G-protein-signalling of FPR2 have been well characterized, molecular mechanisms controlling subsequent events such as endocytosis and recycling to the plasma membrane are less understood. Here we show the key role of the GPCR kinase 5 (GRK5) in facilitating FPR2 endocytosis and post-endocytic trafficking. We found, in response to activation by a synthetic peptide WKYMVm, the recruitment of β-Arrestins to the receptor requires both putative phosphorylation sites in the C-terminal of FPR2 and the presence of GRKs, predominantly GRK5. Furthermore, although GRKs are required for β-Arrestin recruitment and endocytosis, the recruitment of β-Arrestin is not itself essential for FPR2 endocytosis. Instead, β-Arrestin determines post-endocytic delivery of FPR2 to subcellular compartments and subsequent plasma membrane delivery and controls the magnitude of downstream signal transduction. Collectively, the newly characterized FPR2 molecular pharmacology will facilitate the design of more efficient therapeutics targeting chronic inflammation.