Formyl peptide receptor 1 is a cell surface receptorprotein that in humans is encoded by the formyl peptide receptor 1 gene. This gene encodes a G protein-coupled receptorcell surface protein that binds and is activated by N-Formylmethionine-containing oligopeptides, particularly N-Formylmethionine-leucyl-phenylalanine. FPR1 is prominently expressed by mammalian phagocytic and blood leukocyte cells where it functions to mediate these cells' responses to the N-formylmethionine-containing oligopeptides which are released by invading microorganisms and injured tissues. FPR1 directs these cells to sites of invading pathogens or disrupted tissues and then stimulates these cells to kill the pathogens or to remove tissue debris; as such, it is an important component of the innate immune system that operates in host defense and damage control. Humans also express two paralogs of FPR1 vis., FPR2 and FPR3. Mice express no fewer than 7 Fpr receptors and encoding genes that are homologous to FPR1 although no single one of these FPRs appears to perform exactly the same functions as any one of the human FPRs.
Function
FPR1 binds with and is activated by:
bacterial and mitochondrial N-formyl peptides and thereby initiates innate host immune responses.
various synthetic N-formyl and non-formylated peptides that show distinguishing differences from those that interact with FPR2 and FPR3.
T20/DP178 & T21/DP107, N-acetylated polypeptides derived from the gp41HIV-1 envelope protein. This interaction is of unknown physiological significance although peptide T20/DP178 is a licensed anti-retrovirus agent.
Annexin A1 and its N-terminal peptides. At low concentrations, these agents stimulate neutrophils to raise cytosolic Ca2+ levels and thereby activate Ca2+-dependent signaling pathways; however, they do not fully activate the MAPK pathway but rather leave the neutrophil desensitized to chemokine IL-8. At high concentrations, in contrast, the agents fully activate neutrophils and are potent pro-inflammatory stimulants.
History
Studies conducted in the 1970s found that a series of N-formylmethionine-containing oligopeptides, including the most potent and best known member of this series, N-Formylmethionine-leucyl-phenylalanine, stimulated rabbit and human neutrophils by an apparent receptor-dependent mechanism to migrate in a directional pattern in classical laboratory assays of chemotaxis. Since these oligopeptides were produced by bacteria or synthetic analogs of such products, it was suggested that the N-formyl oligopeptides are important chemotatic factors and their receptors are important chemotactic factor receptors that act respectively as signaling and signal-recognizing elements to initiate Inflammation responses in order to defend against bacterial invasion. Further studies cloned a receptor for these N-formyl oligopeptides, FPR1. Two receptors where thereafter discovered and named FPR2 and FPR3 based on the similarity of their genes' predicted amino acid sequence to that of FPR1 rather than on any ability to bind or be activated by the formyl oligopeptides. The latter two receptors were subsequently found to have very different specificities for the formyl oligopeptides and very different functions than those for FPR1. FPR1 is the premiere receptor for the pro-inflammatory actions of formyl peptides.
Nomenclature
Confusingly, there are two nomenclatures for FPR receptors and their genes, the first one used, FPR, FPR1, and FPR2, and its replacement, FPR1, FPR2, and FPR3. The latter nomenclature was recommended by the International Union of Basic and Clinical Pharmacology 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, FPR2A, and ALX/FPR2 ; and for FPR3 are FPRH2, FPRL2, and FMLPY.
Gene
Human
In early studies, cultured human HL-60 promyelocytes purposely differentiated to granulocytes were used to partially purify and in a series of experiments cloneFPR1; an apparent homolog of FPR1, Fpr was also cloned from rabbit neutrophils. The studies indicated that FPR1 is a G protein-coupled receptor that activates cells though a linkage to the pertussis toxin-sensitive Gαi subclass of G proteins, that FPR1 is located on chromosome 19q.13.3, and that this gene consists of two exons, the first of which encodes a 66 base pair 5'-untranslated sequence, the second of which has an intronless open reading frame coding for a protein containing ~354 amino acids; the studies also indicated that cells express multiple formyl peptide receptor mRNA transcripts due to Allelic heterogeneity, alternate Polyadenylation sites, and possibly products of other genes with homology to FPR1. Subsequent studies cloned two other genes with homology to FPR1 viz., FPL2 and FPR3. FPR2 and FPR3 are composed of 351 and 352 amino acids, respectively, and similar to FPR1 have intronless open reading frames which encode G protein coupled receptors; FPR1 and FPR2 have 66% and 56% amino acid sequence identity with FPR1 and 72% homology to each other. All three genes localize to chromosome 19q.13.3 in the order of FPR1, FPR2, and FPR3 to form a cluster which also includes the gene for another G protein-coupled chemotactic factor receptor, the C5a receptor, which binds and is activated by complement component 5a and GPR77, a second C5a anaphylatoxin chemotactic receptor C5a2, a second C5a receptor of debated function which has the structure of a G protein coupled receptor but fails to couple to G proteins. These points are of interest because C5a is generated by the interaction of bacteria with blood plasma components to activate the complement cascade which then cleave C5a from Complement component 5. Thus, bacteria produce a family of oligopeptide chemotactic factors plus activate host complement pathways to generate C5a, which, like the formylated oligopeptides, is a neutrophil chemotactic factor that operates through receptors whose genes cluster with those for the three formly peptide receptors. Furthermore, bacteria-induced complement activation also causes the formation of complement component 3a by cleavage from complement component 3; C3a is a neutrophil chemotactic factor which operates through a G protein coupled chemotactic factor receptor, the C3a receptor, whose gene is located at chromosome 12p13; C3a also acts through C5L2.
Mouse
Mouse formyl peptide receptor genes localize to chromosome 17A3.2 in the following order: Fpr1, Fpr-rs2, Fpr-rs1, Fpr-rs4, Fpr-rs7, Fpr-rs6, and Fpr-rs3; Pseudogenes ψFpr-rs2 and ψFpr-rs3 mouse Fpr1 is an ortholog of human FPR1, responding to many bacterial- and mitochondrial-derived formyl peptides but only minimally to FMLP and having certain pharmacologic properties in common with human FPR2/ALX; b) mouse Fpr2 and mFpr-rs1 bind with high affinity and respond to lipoxins but have little affinity for or responsiveness to formyl peptides and therefore share key properties with human FPR2/ALX; and c) based on its predominantly intracellular distribution, mFpr-rs1 correlates, and therefore may share functionally, with human FPR3; The ψFpr-rs2 gene contains a deletion and frame shift which renders its protein 186 nucleotides shorter but 98% identical to the protein encoded by its closest paralog gene, Fpr-rs2. Since ψFpr-rs2 transcripts are expressed and inducible in multiple mouse tissues and since gene knockout studies ascribe functionality to it, ψFpr-rs2 may not a true pseudogene and, it is suggested, should be renamed Fpr-rs8. Fpr-rs1, Fpr-rs3, Fpr-rs4, Fpr-rs6, and Fpr-rs7 receptors are expressed in the olfactory bulb sensory neurons of the Vomeronasal organ where they have been shown to respond to their known ligands, FMLP and lipoxin A4. Isolated mouse Olfactory bulb neurons also respond to a range of other fpr agonists. These results suggest that the cited receptors function to allow the olfactory-based detection of various contaminated compounds such as spoiled food and/or their many inflammation-regulating and other agonists in bodily secretions.
The large number of mouse compared to human FPR receptors makes it difficult to extrapolate human FPR1 functions based on genetic or other experimental manipulations of FPR receptors in mice. In any event, targeted disruption of the Fpr1 gene reduced the ability of mice to survive intravenous injection of the bacterial pathogen, listeria monocytogenes; disruption of the Fpr2 gene in mice produce a similar effect while disruption of both genes further lowered the survival of mice to the listeria challenge. The effect of these gene knockouts appeared due to faulty leukocyte function and other causes leading to a breakdown in the innate immune response. The functions of the human FPR1 receptor may be equivalent to the overlapping functions of the mouse Fpr1 and Fpr2 functions and therefore be critical in the defense against at least certain bacteria. Targeted disruption of FPR-rs1 produced a 33% reduction in the lifetime of mice; there was no specific pathology associated with this reduction.
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, early duplication of FPR1, and FPR2/FPR3 splitting with FPR3 originating from the latest duplication event near the origin of primates. Rabbits express an ortholog of FPR1 with high binding affinity for FMLP; rats express an ortholog of FPR2 with high affinity for lipoxin A4.
