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]
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]
TheFPR3 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 (seeformyl 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 toFPR1, has an intronless open reading frames which encodes a protein with the 7 transmembrane structure ofG 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, theC5a receptor (also termed CD88) andGPR77, 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]
Mouse FPR receptors localize to chromosome 17A3.2 in the following order:Fpr1,Fpr-rs2 (orfpr2),Fpr-rs1 (orLXA4R),Fpr-rs4,Fpr-rs7, Fpr-rs7,Fpr-rs6, andFpr-rs3;PseudogenesψFpr-rs2 andψFpr-rs3 (orψFpr-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.
FPR receptors are widely distributed throughout mammalian species with the FPR1, FPR2, and FPR3paralogs, based onphylogenetic 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 anortholog 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 forlipoxin A4.[18]
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 ofheme-binding protein 1 bycathepsin D cleavage that potently stimulateschemotaxis 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 byhumanin and thereby may be involved in inhibiting the inflammation occurring in and perhaps contributing toAlzheimer's disease.[27]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.PMID1612600.
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^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.PMID2161213.
^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.PMID2176894.
^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.PMID1690150.S2CID22817786.
^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.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):437–40.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):582–9.doi:10.1016/0006-291x(92)90629-y.PMID1374236.
^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.PMID25561369.S2CID17721865.
^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.PMID15465011.
Yang D, Chen Q, Gertz B, He R, Phulsuksombati M, Ye RD, Oppenheim JJ (Sep 2002). "Human dendritic cells express functional formyl peptide receptor-like-2 (FPRL2) throughout maturation".Journal of Leukocyte Biology.72 (3):598–607.doi:10.1189/jlb.72.3.598.PMID12223529.S2CID41422257.
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.PMID15465011.
Lee HY, Lee SY, Shin EH, Kim SD, Kim JM, Lee MS, Ryu SH, Bae YS (Aug 2007). "F2L, a peptide derived from heme-binding protein, inhibits formyl peptide receptor-mediated signaling".Biochemical and Biophysical Research Communications.359 (4):985–90.doi:10.1016/j.bbrc.2007.06.001.PMID17577578.
