Confusingly, there are two "standard" nomenclatures for FPR receptors and their genes, the first used, FPR, FPR1, and FPR2 and its replacement, FPR1, FPR2 (this gene), and FPR3. The latter nomenclature is recommended by the International Union of Basic and Clinical Pharmacology[8] and is used here. Other previously used names for FPR1 are NFPR, and FMLPR; for FPR2 are FPRH1, FPRL1, RFP, LXA4R, ALXR, FPR2/ALX, HM63, FMLPX, and FPR2A; and for FPR3 are FPRH2, FPRL2, and FMLPY.[8]
Gene
Human
The human FPR2 gene encodes the 351 amino acid receptor, FPR2, within an intronless open reading frame. It forms a cluster with FPR1 and FPR3 genes on chromosome 19q.13.3 in the order of FPR1, FPR2, and FPR3; this cluster also includes the genes for two other chemotactic factor receptors, the G protein-coupled C5a receptor (also termed CD88) and a second C5a receptor, GPR77 (i.e. C5a2 or C5L2), which has the structure of G protein receptors but apparently does not couple to G proteins and is of uncertain function.[9] The FPR1, FPR2, and FPR3 paralogs, based on phylogenetic analysis, originated from a common ancestor with early duplication of FPR1 and FPR2/FPR3 splitting with FPR3 originating from the latest duplication event near the origin of primates.[10]
Mouse
Mice have no less than 7 FPR receptors encoded by 7 genes that localize to chromosome 17A3.2 in the following order: Fpr1, Fpr-rs2 (or fpr2), Fpr-rs1 (or LXA4R), Fpr-rs4, Fpr-rs7, Fpr-rs7, Fpr-rs6, and Fpr-rs3; this locus also contains PseudogenesψFpr-rs2 and ψFpr-rs3 (or ψFpr-rs5) which lie just after Fpr-rs2 and Fpr-rs1, respectively. The 7 mouse FPR receptors have ≥50% amino acid sequence identity with each other as well as with the three human FPR receptors.[11]Fpr2 and mFpr-rs1 bind with high affinity and respond to lipoxins but have little or no affinity for, and responsiveness to, formyl peptides; they thereby share key properties with human FPR2;[12][13][14]
Rat
Rats express an ortholog of FPR2 (74% amino acid sequence identity) with high affinity for lipoxin A4.[11]
Early studies indicated that these peptides act through a receptor-mediated mechanism. To investigate this, researchers used the human leukocyte cell line HL-60, which consists of promyelocytes that do not respond to FMLP. Upon differentiation into granulocytes, which do respond, the cells were used to partially purify[20] and clone a gene. When this gene was transfected into FMLP-unresponsive cells, it conferred responsiveness to FMLP and other N-formyl oligopeptides.[21][22][23][24][25] This receptor was initially named the formyl peptide receptor (FPR). Subsequently, two additional genes were cloned, encoding receptor-like proteins with high sequence similarity to FPR.[26][27][28] These three receptors were initially named inconsistently but are now designated formyl peptide receptor 1 (FPR1), formyl peptide receptor 2 (FPR2; this gene), and formyl peptide receptor 3 (FPR3). FPR2 and FPR3 are grouped with FPR1 based on sequence homology, not ligand specificity.
Indeed, FPR2 exhibits markedly different ligand preferences and biological functions compared to FPR1, while FPR3 does not bind FMLP or most other N-formyl peptides that activate FPR1 or FPR2.[8] A major function of FPR2 is to bind certain specialized pro-resolving mediators (SPMs)—including lipoxin (Lx)A4, AT-LxA4 (arachidonic acid metabolites), and resolvin D1 (RvD1), RvD2, and AT-RvD1 (derived from docosahexaenoic acid)—and to mediate their inflammation-resolving effects. In addition, FPR2 also responds to a wide range of peptides and proteins that may promote inflammation or regulate unrelated processes. The physiological role of FPR3 remains unclear.
Knockout studies
The large number of mouse compared to human FPR receptors makes it difficult to extrapolate human FPR functions based on genetic (e.g. gene knockout or forced overexpression) or other experimental manipulations of the FPR receptors in mice. In any event, combined disruption of the Fpr2 and Fpr3 genes causes mice to mount enhanced acute inflammatory responses as evidenced in three models, intestine inflammation caused by mesenteric artery ischemia-reperfusion, paw swelling caused by carrageenan injection, and arthritis caused by the intraperatoneal injection of arthritis-inducing serum.[29] Since Fpr2 gene knockout mice exhibit a faulty innate immune response to intravenous listeria monocytogenes injection,[30] these results suggest that the human FPR2 receptor and mouse Fpr3 receptor have equivalent functions in dampening at least certain inflammatory response.
Endogenous ligands
FPR2, also known as the LXA4 receptor or ALX/FPR2, was initially identified as a high-affinity receptor for the arachidonic acid metabolite lipoxin A4 (LXA4). It was later found to also bind the related metabolites aspirin-triggered lipoxin A4 (ATL, or 15-epi-LXA4), and the docosahexaenoic acid derivative resolvin D1 (RvD1). These three lipid mediators act to inhibit and resolve inflammation.[31][32][33][34][35]
Originally classified as an orphan receptor and termed RFP, FPR2 was discovered by screening myeloid cell-derived libraries using a formyl-methionyl-leucyl-phenylalanine (FMLP)-like probe.[22][27][36]
In addition to LXA4, ATL, RvD1, and FMLP, FPR2 interacts with a wide range of polypeptides, proteins, and their derivatives. These ligands contribute to processes beyond inflammation, including obesity, neurodegeneration, reproduction, and cancer.[37] Nevertheless, FPR2 is best known for mediating the anti-inflammatory and pro-resolving actions of lipoxins and resolvins.[38][39]
A partial list of FPR2/ALX ligands and their proposed inflammatory effects (based on in vitro and animal studies) includes:
Bacterial and mitochondrial N-formyl peptides such as FMLP – pro-inflammatory (though possibly less physiologically significant than lipid-derived ligands);
↑ Scanzano A, Schembri L, Rasini E, Luini A, Dallatorre J, Legnaro M, etal. (Feb 2015). "Adrenergic modulation of migration, CD11b and CD18 expression, ROS and interleukin-8 production by human polymorphonuclear leukocytes". Inflammation Research. 64 (2): 127–135. doi:10.1007/s00011-014-0791-8. PMID25561369. S2CID17721865.
↑ Boulay F, Tardif M, Brouchon L, Vignais P (May 1990). "Synthesis and use of a novel N-formyl peptide derivative to isolate a human N-formyl peptide receptor cDNA". Biochemical and Biophysical Research Communications. 168 (3): 1103–1109. Bibcode:1990BBRC..168.1103B. doi:10.1016/0006-291x(90)91143-g. PMID2161213.
1 2 Boulay F, Tardif M, Brouchon L, Vignais P (Dec 1990). "The human N-formylpeptide receptor. Characterization of two cDNA isolates and evidence for a new subfamily of G-protein-coupled receptors". Biochemistry. 29 (50): 11123–11133. doi:10.1021/bi00502a016. PMID2176894.
↑ Perez HD, Holmes R, Kelly E, McClary J, Chou Q, Andrews WH (Nov 1992). "Cloning of the gene coding for a human receptor for formyl peptides. Characterization of a promoter region and evidence for polymorphic expression". Biochemistry. 31 (46): 11595–11599. doi:10.1021/bi00161a044. PMID1445895.
↑ Bao L, Gerard NP, Eddy RL, Shows TB, Gerard C (Jun 1992). "Mapping of genes for the human C5a receptor (C5AR), human FMLP receptor (FPR), and two FMLP receptor homologue orphan receptors (FPRH1, FPRH2) to chromosome 19". Genomics. 13 (2): 437–440. doi:10.1016/0888-7543(92)90265-t. PMID1612600.
↑ Ye RD, Cavanagh SL, Quehenberger O, Prossnitz ER, Cochrane CG (Apr 1992). "Isolation of a cDNA that encodes a novel granulocyte N-formyl peptide receptor". Biochemical and Biophysical Research Communications. 184 (2): 582–589. Bibcode:1992BBRC..184..582Y. doi:10.1016/0006-291x(92)90629-y. PMID1374236.
↑ Perez HD, Holmes R, Kelly E, McClary J, Andrews WH (Sep 1992). "Cloning of a cDNA encoding a receptor related to the formyl peptide receptor of human neutrophils". Gene. 118 (2): 303–304. doi:10.1016/0378-1119(92)90208-7. PMID1511907.
Ye RD, Cavanagh SL, Quehenberger O, Prossnitz ER, Cochrane CG (Apr 1992). "Isolation of a cDNA that encodes a novel granulocyte N-formyl peptide receptor". Biochemical and Biophysical Research Communications. 184 (2): 582–589. Bibcode:1992BBRC..184..582Y. doi:10.1016/0006-291X(92)90629-Y. PMID1374236.
Perez HD, Holmes R, Kelly E, McClary J, Andrews WH (Sep 1992). "Cloning of a cDNA encoding a receptor related to the formyl peptide receptor of human neutrophils". Gene. 118 (2): 303–304. doi:10.1016/0378-1119(92)90208-7. PMID1511907.
Bao L, Gerard NP, Eddy RL, Shows TB, Gerard C (Jun 1992). "Mapping of genes for the human C5a receptor (C5AR), human FMLP receptor (FPR), and two FMLP receptor homologue orphan receptors (FPRH1, FPRH2) to chromosome 19". Genomics. 13 (2): 437–440. doi:10.1016/0888-7543(92)90265-T. PMID1612600.
Nomura H, Nielsen BW, Matsushima K (Oct 1993). "Molecular cloning of cDNAs encoding a LD78 receptor and putative leukocyte chemotactic peptide receptors". International Immunology. 5 (10): 1239–1249. doi:10.1093/intimm/5.10.1239. PMID7505609.
Durstin M, Gao JL, Tiffany HL, McDermott D, Murphy PM (May 1994). "Differential expression of members of the N-formylpeptide receptor gene cluster in human phagocytes". Biochemical and Biophysical Research Communications. 201 (1): 174–179. Bibcode:1994BBRC..201..174D. doi:10.1006/bbrc.1994.1685. PMID8198572.
Deng X, Ueda H, Su SB, Gong W, Dunlop NM, Gao JL, etal. (Aug 1999). "A synthetic peptide derived from human immunodeficiency virus type 1 gp120 downregulates the expression and function of chemokine receptors CCR5 and CXCR4 in monocytes by activating the 7-transmembrane G-protein-coupled receptor FPRL1/LXA4R". Blood. 94 (4): 1165–1173. doi:10.1182/blood.V94.4.1165. PMID10438703.
Kang Y, Taddeo B, Varai G, Varga J, Fiore S (Nov 2000). "Mutations of serine 236-237 and tyrosine 302 residues in the human lipoxin A4 receptor intracellular domains result in sustained signaling". Biochemistry. 39 (44): 13551–13557. doi:10.1021/bi001196i. PMID11063592.
Svensson L, Dahlgren C, Wennerås C (Oct 2002). "The chemoattractant Trp-Lys-Tyr-Met-Val-D-Met activates eosinophils through the formyl peptide receptor and one of its homologues, formyl peptide receptor-like 1". Journal of Leukocyte Biology. 72 (4): 810–818. doi:10.1189/jlb.72.4.810. PMID12377951. S2CID45789067.
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