The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview

Abstract

Leukocyte recruitment to sites of inflammation and infection is dependent on the presence of a gradient of locally produced chemotactic factors. This review is focused on current knowledge about the activation and regulation of chemoattractant receptors. Emphasis is placed on the members of the N-formyl peptide receptor family, namely FPR (N-formyl peptide receptor), FPRL1 (FPR like-1) and FPRL2 (FPR like-2), and the complement fragment C5a receptors (C5aR and C5L2). Upon chemoattractant binding, the receptors transduce an activation signal through a G protein-dependent pathway, leading to biochemical responses that contribute to physiological defense against bacterial infection and tissue damage. C5aR, and the members of the FPR family that were previously thought to be restricted to phagocytes proved to have a much broader spectrum of cell expression. In addition to N-formylated peptides, numerous unrelated ligands were recently found to interact with FPR and FPRL1. Novel agonists include both pathogen- and host-derived components, and synthetic peptides. Antagonistic molecules have been identified that exhibit limited receptor specificity. How distinct ligands can both induce different biological responses and produce different modes of receptor activation and unique sets of cellular responses are discussed. Cell responses to chemoattractants are tightly regulated at the level of the receptors. This review describes in detail the regulation of receptor signalling and the multi-step process of receptor inactivation. New concepts, such as receptor oligomerization and receptor clustering, are considered. Although FPR, FPRL1 and C5aR trigger similar biological functions and undergo a rapid chemoattractant-mediated phosphorylation, they appear to be differentially regulated and experience different intracellular fates.

Fig. 1

Alignment of the amino acid sequence of the C5a receptor and C5L2, a non-signalling C5a receptor. Residues that are identical are highlighted in green, whereas homologous amino acids are highlighted in yellow. The transmembrane α-helices are underlined.

Fig. 2

Schematic summary of the main signalling pathways initiated by C5aR and N-formyl peptide receptors in myeloid cells. Agonist binding to the receptors results in dissociation of heterotrimeric G protein into Gα-GTP and Gβγ subunits which activate downstream effectors and signalling cascades (see text for details) involved in the regulation of cellular functions (chemotaxis, superoxide production and release of inflammatory mediators). AA, arachidonic acid; PA, phosphatidic acid. Other abbreviations are mentioned in the text.

Fig. 3

Alignment of the carboxyl-terminal portions of the C5aR and the members of the FPR family. Serine and threonine residues are indicated in bold. The amino acids identified as the major sites of phosphorylation upon agonist binding are pointed with a red star in the case of C5aR and FPR. The sites phosphorylated in FPRL1 and FPRL2 have not yet been identified. In C5aR, serine residues at positions 332, 334, and 338 (highlighted in green) are critical for both C5a-mediated phosphorylation and C5a-mediated intracellular trafficking of the C5aR-β-arrestin complex. In FPR, the phosphorylation of serines and threonine residues at positions 328, 329, 331, and 332 (highlighted in yellow) is required for the subsequent phosphorylation of the other serine and threonine residues. The residues at positions 328, 332, and 338 are for β-arrestin binding and internalization. The two putative GRK-mediated phosphorylation sites in FPR are underlined in red and blue.

Fig. 4

Intracellular trafficking of activated receptors. Agonist dependent phosphorylation of the receptors leads to the recruitment of β-arrestins. The receptor–β-arrestin complex is targeted to clathrin-coated pits, traffics in early endosomes and accumulates in a perinuclear recycling compartment. After dephosphorylation and dissociation from β-arrestins, the receptors resensitize and recycle to the cell surface. In the case of C5aR, a fraction of the internalized receptor is targeted to lysosomes for degradation.