N-formyl peptide receptor 3 (FPR3) is a receptor protein that in humans is encoded by the FPR3 gene.[3][4][5]
Quick Facts FPR3, Identifiers ...
Close
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]
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]
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]
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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.
- Christophe T, Karlsson A, Dugave C, Rabiet MJ, Boulay F, Dahlgren C (Jun 2001). "The synthetic peptide Trp-Lys-Tyr-Met-Val-Met-NH2 specifically activates neutrophils through FPRL1/lipoxin A4 receptors and is an agonist for the orphan monocyte-expressed chemoattractant receptor FPRL2". The Journal of Biological Chemistry. 276 (24): 21585–93. doi:10.1074/jbc.M007769200. PMID 11285256.
- 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. PMID 12223529. S2CID 41422257.
- Christophe T, Karlsson A, Rabiet MJ, Boulay F, Dahlgren C (Nov 2002). "Phagocyte activation by Trp-Lys-Tyr-Met-Val-Met, acting through FPRL1/LXA4R, is not affected by lipoxin A4". Scandinavian Journal of Immunology. 56 (5): 470–6. doi:10.1046/j.1365-3083.2002.01149.x. PMID 12410796.
- Ernst S, Lange C, Wilbers A, Goebeler V, Gerke V, Rescher U (Jun 2004). "An annexin 1 N-terminal peptide activates leukocytes by triggering different members of the formyl peptide receptor family". Journal of Immunology. 172 (12): 7669–76. doi:10.4049/jimmunol.172.12.7669. PMID 15187149.
- 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.
- Kang HK, Lee HY, Kim MK, Park KS, Park YM, Kwak JY, Bae YS (Jul 2005). "The synthetic peptide Trp-Lys-Tyr-Met-Val-D-Met inhibits human monocyte-derived dendritic cell maturation via formyl peptide receptor and formyl peptide receptor-like 2". Journal of Immunology. 175 (2): 685–92. doi:10.4049/jimmunol.175.2.685. PMID 16002663.
- 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. PMID 17577578.
