Formyl peptide receptor 3 explained

N-formyl peptide receptor 3 (FPR3) is a receptor protein that in humans is encoded by the FPR3 gene.[1] [2] [3]

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[4] 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.[4]

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.[5] [6]

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)[7] [8] [9] [10] [11] [12] [13] [14] 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.[4] 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.[15]

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.[16] Based on its predominantly intracellular distribution, mFpr-rs1 correlates, and therefore may share functionality, with human FPR3;[17] [18] [19] 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.[20] 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.[16]

Cellular and tissue distribution

FPL3 is expressed by circulating monocytes, eosinophils, and basophils but not neutrophils; tissue macrophages and dendritic cells.[16] [21] [22]

Ligands and potential ligand-based disease related activities

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.[23] 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.[24] F2L thereby may be a pro-inflammatory stimulus for FPR3.[6] 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.[25]

See also

Further reading

External links

Notes and References

  1. Bao L, Gerard NP, Eddy RL, Shows TB, Gerard C . 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 . Jun 1992 . 1612600 . 10.1016/0888-7543(92)90265-T .
  2. Durstin M, Gao JL, Tiffany HL, McDermott D, Murphy PM . Differential expression of members of the N-formylpeptide receptor gene cluster in human phagocytes . Biochemical and Biophysical Research Communications . 201 . 1 . 174–9 . May 1994 . 8198572 . 10.1006/bbrc.1994.1685 .
  3. Web site: Entrez Gene: FPRL2 formyl peptide receptor-like 2.
  4. Ye RD, Boulay F, Wang JM, Dahlgren C, Gerard C, Parmentier M, Serhan CN, Murphy PM . International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family . Pharmacological Reviews . 61 . 2 . 119–61 . Jun 2009 . 19498085 . 10.1124/pr.109.001578 . 2745437.
  5. Rabiet MJ, Macari L, Dahlgren C, Boulay F . 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 . Jul 2011 . 21543323 . 10.1074/jbc.M111.244590 . 3143635. free .
  6. Dorward DA, Lucas CD, Chapman GB, Haslett C, Dhaliwal K, Rossi AG . 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 . May 2015 . 25791526 . 10.1016/j.ajpath.2015.01.020 . 4419282.
  7. Boulay F, Tardif M, Brouchon L, Vignais P . 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 . May 1990 . 2161213 . 10.1016/0006-291x(90)91143-g.
  8. Boulay F, Tardif M, Brouchon L, Vignais P . 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 . Dec 1990 . 2176894 . 10.1021/bi00502a016.
  9. Murphy PM, Gallin EK, Tiffany HL, Malech HL . The formyl peptide chemoattractant receptor is encoded by a 2 kilobase messenger RNA. Expression in Xenopus oocytes . FEBS Letters . 261 . 2 . 353–7 . Feb 1990 . 1690150 . 10.1016/0014-5793(90)80590-f. 22817786 .
  10. Coats WD, Navarro J . Functional reconstitution of fMet-Leu-Phe receptor in Xenopus laevis oocytes . The Journal of Biological Chemistry . 265 . 11 . 5964–6 . Apr 1990 . 10.1016/S0021-9258(19)39276-2 . 2156834 . free .
  11. Perez HD, Holmes R, Kelly E, McClary J, Chou Q, Andrews WH . 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 . Nov 1992 . 1445895 . 10.1021/bi00161a044.
  12. Bao L, Gerard NP, Eddy RL, Shows TB, Gerard C . 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 . Jun 1992 . 1612600 . 10.1016/0888-7543(92)90265-t.
  13. Murphy PM, Ozçelik T, Kenney RT, Tiffany HL, McDermott D, Francke U . 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 . Apr 1992 . 10.1016/S0021-9258(18)42563-X . 1373134 . free .
  14. Ye RD, Cavanagh SL, Quehenberger O, Prossnitz ER, Cochrane CG . Isolation of a cDNA that encodes a novel granulocyte N-formyl peptide receptor . Biochemical and Biophysical Research Communications . 184 . 2 . 582–9 . Apr 1992 . 1374236 . 10.1016/0006-291x(92)90629-y.
  15. Li R, Coulthard LG, Wu MC, Taylor SM, Woodruff TM . C5L2: a controversial receptor of complement anaphylatoxin, C5a . FASEB Journal . 27 . 3 . 855–64 . Mar 2013 . 23239822 . 10.1096/fj.12-220509 . free . 24870278 .
  16. Migeotte I, Communi D, Parmentier M . Formyl peptide receptors: a promiscuous subfamily of G protein-coupled receptors controlling immune responses . Cytokine & Growth Factor Reviews . 17 . 6 . 501–19 . Dec 2006 . 17084101 . 10.1016/j.cytogfr.2006.09.009 .
  17. He HQ, Liao D, Wang ZG, Wang ZL, Zhou HC, Wang MW, Ye RD . Functional characterization of three mouse formyl peptide receptors . Molecular Pharmacology . 83 . 2 . 389–98 . Feb 2013 . 23160941 . 10.1124/mol.112.081315 . 4170117.
  18. Takano T, Fiore S, Maddox JF, Brady HR, Petasis NA, Serhan CN . 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 . May 1997 . 9151906 . 10.1084/jem.185.9.1693 . 2196289.
  19. Vaughn MW, Proske RJ, Haviland DL . Identification, cloning, and functional characterization of a murine lipoxin A4 receptor homologue gene . Journal of Immunology . 169 . 6 . 3363–9 . Sep 2002 . 12218158 . 10.4049/jimmunol.169.6.3363. free .
  20. Muto Y, Guindon S, Umemura T, Kőhidai L, Ueda H . Adaptive evolution of formyl peptide receptors in mammals . Journal of Molecular Evolution . 80 . 2 . 130–41 . Feb 2015 . 25627928 . 10.1007/s00239-015-9666-z . 2015JMolE..80..130M . 14266716 .
  21. de Paulis A, Prevete N, Fiorentino I, Walls AF, Curto M, Petraroli A, Castaldo V, Ceppa P, Fiocca R, Marone G . 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 . Jun 2004 . 15187157 . 10.4049/jimmunol.172.12.7734. free .
  22. Scanzano A, Schembri L, Rasini E, Luini A, Dallatorre J, Legnaro M, Bombelli R, Congiu T, Cosentino M, Marino F . Adrenergic modulation of migration, CD11b and CD18 expression, ROS and interleukin-8 production by human polymorphonuclear leukocytes . Inflammation Research . 64 . 2 . 127–35 . Feb 2015 . 25561369 . 10.1007/s00011-014-0791-8 . 17721865 .
  23. Rabiet MJ, Huet E, Boulay F . 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 . Aug 2005 . 16025565 . 10.1002/eji.200526338 . free .
  24. 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 . Identification and characterization of an endogenous chemotactic ligand specific for FPRL2 . The Journal of Experimental Medicine . 201 . 1 . 83–93 . Jan 2005 . 15623572 . 10.1084/jem.20041277 . 2212760.
  25. Harada M, Habata Y, Hosoya M, Nishi K, Fujii R, Kobayashi M, Hinuma S . N-Formylated humanin activates both formyl peptide receptor-like 1 and 2 . Biochemical and Biophysical Research Communications . 324 . 1 . 255–61 . Nov 2004 . 15465011 . 10.1016/j.bbrc.2004.09.046 .

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