FPR3 gene

The FPR3 gene (FPR3 stands for: formyl peptide receptor 3) is a protein-coding gene located on chromosome 19q13.41. Associated pathways include class A/1 (rhodopsin-like receptors) and GPCR downstream signaling pathway. Gene Ontology (GO) annotations to this gene include G protein-coupled receptor activity and N-formyl peptide receptor activity. Important paralogs of this gene are FPR1/2.

The formyl peptide receptor family, FPR1, FPR2 and FPR3, are G-protein-coupled receptors that are mainly expressed by mammalian phagocytic leukocytes. FPRs are involved in antibacterial defense and inflammatory responses of the host organism (Sun R et al. 2004).

The receptor protein encoded by the FPR3 gene, formyl peptide receptor 3, is localized in the cell membrane and is likely involved in several processes, including complement receptor-mediated signaling, phospholipase C-activating G protein-coupled receptor signaling, and positive regulation of cytosolic calcium ion concentration. The protein is likely to act upstream or within the G protein-coupled receptor signaling pathway.

Formyl peptide receptor 3 is the receptor with low affinity for N-formyl-methionyl peptides, which are potent chemotactic factors for neutrophils, within the formyl peptide receptor family with the 3 members FPR1-3. The binding of FMLP to the receptor leads to the activation of neutrophils. This response is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. Acts as a receptor for humanin (Harada M et al. 2004).

Data obtained from dendritic cells (DCs) demonstrate significant differences in the expression of formyl peptide receptors (FPRs). In DCs, only the peptides generated during the degradation of allergenic lipocalins were able to bind to the FPR3 receptor protein, whereas this was not possible for peptides generated during the degradation of non-allergenic lipocalins. It can be assumed that the binding of allergenic lipocalins to FPR3 could be a mechanism for the induction of allergic immune responses (Gruber RW. 2020)

FPR3 and lipocalins colocalize in the same vesicles in DCs. Cathepsin S-digested allergenic lipocalins, but not products of non-allergenic homologs (Klaver D et al. 2020). Silencing of FPR3 in DCs or pretreatment with an antagonistic peptide restores IL-12 expression and induces IL-10 expression by DCs treated with lipocalin allergens, thereby attenuating the TH2 shift and inducing IL-10 production in cocultured TH cells.

FPR antagonists could represent a new option for the therapy of allergies (Klaver D et al. 2020).

1. Boulay F et al. (1990) Synthesis and use of a novel N-formyl peptide derivative to isolate a human N-formyl peptide receptor cDNA. Biochem Biophys Res Commun 168:1103-1109.
2. Gruber RW (2020) Journal Club. JDDG 18: 181
3. Harada M et al. (2004) N-Formylated humanin activates both formyl peptide receptor-like 1 and 2. Biochem Biophys Res Commun 324:255-261.
4. Klaver D et al. (2020) Peptides from allergenic lipocalins bind to formyl peptide receptor 3 in human dendritic cells to mediate TH2 immunity. J Allergy Clin Immunol 145:654-665.
5. Maestes DC et al.(1999) Differential phosphorylation paradigms dictate desensitization and internalization of the N-formyl peptide receptor. J Biol Chem 274:29791-2975.
6. Sun R et al. (2004) Identification of neutrophil granule protein cathepsin G as a novel chemotactic agonist for the G protein-coupled formyl peptide receptor. J Immunol 173:428-436.