Formyl peptide receptor 3

N-formyl peptide receptor 3 (FPR3) is a receptor protein that in humans is encoded by the FPR3 gene.[3][4][5]

FPR3
Identifiers
AliasesFPR3, FML2_HUMAN, FMLPY, FPRH1, FPRH2, FPRL2, RMLP-R-I, FMLP-R-II, formyl peptide receptor 3
External IDsOMIM: 136539 HomoloGene: 130500 GeneCards: FPR3
Orthologs
SpeciesHumanMouse
Entrez

2359

n/a

Ensembl

ENSG00000187474

n/a

UniProt

P25089

n/a

RefSeq (mRNA)

NM_002030

n/a

RefSeq (protein)

NP_002021

n/a

Location (UCSC)Chr 19: 51.8 – 51.83 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Nomenclature note

Confusingly, there are two nomenclatures for FPR receptors and their genes, the first one used, FPR, FPR1, and FPR2 and its replacement (which corresponds directly to these three respective receptors and their genes), FPR1, FPR2, and FPR3. The latter nomenclature is recommended by the International Union of Basic and Clinical Pharmacology[6] 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.[6]

FPR3 function

The overall function of FPR3 is quite unclear. Compared to FPR1 and FPR2, FPR3 is highly phosphorylated (a signal for receptor inactivation and internalization) and more localized to small intracellular vesicles. This suggests that FPR3 rapidly internalizes after binding its ligands and thereby may serve as a "decoy" receptor to reduce the binding of its ligands to FRP1 and FRP2 receptors.[7][8]

Genes

Humans

The FPR3 gene was cloned and named based on the similarity of the amino acid sequence which it encodes to that encoded by the gene for FPR1 (see formyl peptide receptor 1 for details)[9][10][11][12][13][14][15][16] The studies indicated that FPR3 is composed of 352 amino acids and its gene, similar to FPR1, has an intronless open reading frames which encodes a protein with the 7 transmembrane structure of G protein coupled receptors; FPR3 has 69% and 72% amino acid sequence identities with FPR1.[6] All three genes localize to chromosome 19q.13.3 in the order of FPR1 (19q13.410), FPR2 (19q13.3-q13.4), and FPR3 (19q13.3-q13.4) to form a cluster which also includes the genes for another G protein-coupled chemotactic factor receptor, the C5a receptor (also termed CD88) and GPR77, and a second C5a receptor, C5a2 (C5L2), which has the structure of a G protein coupled receptor but fails to couple to G proteins and is of debated function.[17]

Mice

Mouse FPR receptors 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; Pseudogenes ψFpr-rs2 and ψFpr-rs3 (or ψFpr-rs5) lie just after Fpr-rs2 and Fpr-rs1, respectively. All of the active mouse FPR receptors have ≥50% amino acid sequence identity with each other as well as with the three human FPR receptors.[18] Based on its predominantly intracellular distribution, mFpr-rs1 correlates, and therefore may share functionality, with human FPR3;[19][20][21] However, 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.

Other species

FPR receptors are widely distributed throughout mammalian species with the FPR1, FPR2, and FPR3 paralogs, based on phylogenetic analysis, originating from a common ancestor and early duplication of FPR1 and FPR2/FPR3 splitting with FPR3 originating from the latest duplication event near the origin of primates.[22] Rabbits express an ortholog of FPR1 (78% amino acid sequence identity) with high binding affinity for FMLP; rats express an ortholog of FPR2 (74% amino acid sequence identity) with high affinity for lipoxin A4.[18]

Cellular and tissue distribution

FPL3 is expressed by circulating monocytes, eosinophils, and basophils but not neutrophils; tissue macrophages and dendritic cells.[18][23][24]

The functions of FPR3 and the few ligands which activate it have not been fully clarified. Despite its homology to FPR1, FPR3 is unresponsive to many FPR1-stimulating formyl peptides including FMLP. However, fMMYALF, a N-formyl hexapeptide derived from the mitochondrial protein, NADH dehydrogenase subunit 6, is a weak agonist for FPR3 but >100-fold more potent in stimulating FPR1 and FPR2.[25] F2L is a naturally occurring acylated peptide derived from the N-terminal sequence of heme-binding protein 1 by cathepsin D cleavage that potently stimulates chemotaxis through FPR3 in monocytes and monocyte-derived dendritic cells.[26] F2L thereby may be a pro-inflammatory stimulus for FPR3.[8] Similar to FPR2 (see FPR2 section), FPR3 is activated by humanin and thereby may be involved in inhibiting the inflammation occurring in and perhaps contributing to Alzheimer's disease.[27]

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000187474 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 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): 437–40. doi:10.1016/0888-7543(92)90265-T. PMID 1612600.
  4. 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): 174–9. doi:10.1006/bbrc.1994.1685. PMID 8198572.
  5. "Entrez Gene: FPRL2 formyl peptide receptor-like 2".
  6. Ye RD, Boulay F, Wang JM, Dahlgren C, Gerard C, Parmentier M, Serhan CN, Murphy PM (Jun 2009). "International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family". Pharmacological Reviews. 61 (2): 119–61. doi:10.1124/pr.109.001578. PMC 2745437. PMID 19498085.
  7. Rabiet MJ, Macari L, Dahlgren C, Boulay F (Jul 2011). "N-formyl peptide receptor 3 (FPR3) departs from the homologous FPR2/ALX receptor with regard to the major processes governing chemoattractant receptor regulation, expression at the cell surface, and phosphorylation". The Journal of Biological Chemistry. 286 (30): 26718–31. doi:10.1074/jbc.M111.244590. PMC 3143635. PMID 21543323.
  8. Dorward DA, Lucas CD, Chapman GB, Haslett C, Dhaliwal K, Rossi AG (May 2015). "The Role of Formylated Peptides and Formyl Peptide Receptor 1 in Governing Neutrophil Function during Acute Inflammation". The American Journal of Pathology. 185 (5): 1172–1184. doi:10.1016/j.ajpath.2015.01.020. PMC 4419282. PMID 25791526.
  9. 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): 1103–9. doi:10.1016/0006-291x(90)91143-g. PMID 2161213.
  10. 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): 11123–33. doi:10.1021/bi00502a016. PMID 2176894.
  11. Murphy PM, Gallin EK, Tiffany HL, Malech HL (Feb 1990). "The formyl peptide chemoattractant receptor is encoded by a 2 kilobase messenger RNA. Expression in Xenopus oocytes". FEBS Letters. 261 (2): 353–7. doi:10.1016/0014-5793(90)80590-f. PMID 1690150.
  12. Coats WD, Navarro J (Apr 1990). "Functional reconstitution of fMet-Leu-Phe receptor in Xenopus laevis oocytes". The Journal of Biological Chemistry. 265 (11): 5964–6. doi:10.1016/S0021-9258(19)39276-2. PMID 2156834.
  13. 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): 11595–9. doi:10.1021/bi00161a044. PMID 1445895.
  14. 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): 437–40. doi:10.1016/0888-7543(92)90265-t. PMID 1612600.
  15. Murphy PM, Ozçelik T, Kenney RT, Tiffany HL, McDermott D, Francke U (Apr 1992). "A structural homologue of the N-formyl peptide receptor. Characterization and chromosome mapping of a peptide chemoattractant receptor family". The Journal of Biological Chemistry. 267 (11): 7637–43. doi:10.1016/S0021-9258(18)42563-X. PMID 1373134.
  16. 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): 582–9. doi:10.1016/0006-291x(92)90629-y. PMID 1374236.
  17. Li R, Coulthard LG, Wu MC, Taylor SM, Woodruff TM (Mar 2013). "C5L2: a controversial receptor of complement anaphylatoxin, C5a". FASEB Journal. 27 (3): 855–64. doi:10.1096/fj.12-220509. PMID 23239822. S2CID 24870278.
  18. Migeotte I, Communi D, Parmentier M (Dec 2006). "Formyl peptide receptors: a promiscuous subfamily of G protein-coupled receptors controlling immune responses". Cytokine & Growth Factor Reviews. 17 (6): 501–19. doi:10.1016/j.cytogfr.2006.09.009. PMID 17084101.
  19. He HQ, Liao D, Wang ZG, Wang ZL, Zhou HC, Wang MW, Ye RD (Feb 2013). "Functional characterization of three mouse formyl peptide receptors". Molecular Pharmacology. 83 (2): 389–98. doi:10.1124/mol.112.081315. PMC 4170117. PMID 23160941.
  20. Takano T, Fiore S, Maddox JF, Brady HR, Petasis NA, Serhan CN (May 1997). "Aspirin-triggered 15-epi-lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors". The Journal of Experimental Medicine. 185 (9): 1693–704. doi:10.1084/jem.185.9.1693. PMC 2196289. PMID 9151906.
  21. Vaughn MW, Proske RJ, Haviland DL (Sep 2002). "Identification, cloning, and functional characterization of a murine lipoxin A4 receptor homologue gene". Journal of Immunology. 169 (6): 3363–9. doi:10.4049/jimmunol.169.6.3363. PMID 12218158.
  22. Muto Y, Guindon S, Umemura T, Kőhidai L, Ueda H (Feb 2015). "Adaptive evolution of formyl peptide receptors in mammals". Journal of Molecular Evolution. 80 (2): 130–41. Bibcode:2015JMolE..80..130M. doi:10.1007/s00239-015-9666-z. PMID 25627928. S2CID 14266716.
  23. de Paulis A, Prevete N, Fiorentino I, Walls AF, Curto M, Petraroli A, Castaldo V, Ceppa P, Fiocca R, Marone G (Jun 2004). "Basophils infiltrate human gastric mucosa at sites of Helicobacter pylori infection, and exhibit chemotaxis in response to H. pylori-derived peptide Hp(2-20)". Journal of Immunology. 172 (12): 7734–43. doi:10.4049/jimmunol.172.12.7734. PMID 15187157.
  24. Scanzano A, Schembri L, Rasini E, Luini A, Dallatorre J, Legnaro M, Bombelli R, Congiu T, Cosentino M, Marino F (Feb 2015). "Adrenergic modulation of migration, CD11b and CD18 expression, ROS and interleukin-8 production by human polymorphonuclear leukocytes". Inflammation Research. 64 (2): 127–35. doi:10.1007/s00011-014-0791-8. PMID 25561369. S2CID 17721865.
  25. Rabiet MJ, Huet E, Boulay F (Aug 2005). "Human mitochondria-derived N-formylated peptides are novel agonists equally active on FPR and FPRL1, while Listeria monocytogenes-derived peptides preferentially activate FPR". European Journal of Immunology. 35 (8): 2486–95. doi:10.1002/eji.200526338. PMID 16025565.
  26. Migeotte I, Riboldi E, Franssen JD, Grégoire F, Loison C, Wittamer V, Detheux M, Robberecht P, Costagliola S, Vassart G, Sozzani S, Parmentier M, Communi D (Jan 2005). "Identification and characterization of an endogenous chemotactic ligand specific for FPRL2". The Journal of Experimental Medicine. 201 (1): 83–93. doi:10.1084/jem.20041277. PMC 2212760. PMID 15623572.
  27. Harada M, Habata Y, Hosoya M, Nishi K, Fujii R, Kobayashi M, Hinuma S (Nov 2004). "N-Formylated humanin activates both formyl peptide receptor-like 1 and 2". Biochemical and Biophysical Research Communications. 324 (1): 255–61. doi:10.1016/j.bbrc.2004.09.046. PMID 15465011.

Further reading
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