Disease relevance of Fpr1

• Members of the formyl peptide receptor family recognize chemotactic peptides as well the amyloïd-beta peptide and fragments of the human immunodeficiency virus envelope and may thus be implicated in major pathologies [1].
• FPR-/- mice developed normally, but had increased susceptibility to challenge with Listeria monocytogenes, as measured by increased mortality compared with wild-type littermates [2].
• In a model of mouse peritonitis, FPR antagonists abrogated the anti-migratory effects of peptides Ac2-26 and Ac2-12, with a partial reduction in annexin 1 effects [3].
• These data demonstrate that a complex chemokine network is activated in response to pulmonary pneumococcal infection, and also suggest an important role for fMLP receptor in monocyte/macrophage recruitment in that model [4].
• The activity of these novel PAMPs was sensitive to pertussis toxin but insensitive to the formyl peptide receptor inhibitor CHIPS [5].

Psychiatry related information on Fpr1

• Human formyl peptide receptor (FPR)-like 1 (FPRL1) and its mouse homologue mFPR2 are functional receptors for a variety of exogenous and host-derived chemotactic peptides, including amyloid beta 1-42 (Abeta(42)), a pathogenic factor in Alzheimer's disease [6].

High impact information on Fpr1

• Consistent with this, fMLF induced two distinct concentration optima for chemotaxis of normal mouse neutrophils, but only the high concentration optimum for chemotaxis of neutrophils from FPR knockout mice [7].
• Consistent with this, neutrophil chemotaxis in vitro and neutrophil mobilization into peripheral blood in vivo in response to the prototype N-formylpeptide fMLF (formyl-methionyl-leucyl-phenylalanine) were both absent in FPR-/- mice [2].
• The N-formylpeptide receptor (FPR) is a G protein-coupled receptor that mediates mammalian phagocyte chemotactic responses to bacterial N-formylpeptides [7].
• FPR-/- mice also had increased bacterial load in spleen and liver 2 d after infection, which is before development of a specific cellular immune response, suggesting a defect in innate immunity [2].
• When expressed in Chinese hamster ovary cells, the mouse LXA4R showed specific binding to [3H]LXA4 (K(d) approximately 1.5 nM), and with LXA4 activated GTP hydrolysis [8].

Chemical compound and disease context of Fpr1

• In bleomycin-induced lung fibrosis in mice, administration of a thromboxane synthetase inhibitor DP-1904 increased LXA4 receptor mRNA and decreased type I collagen mRNA [9].

Biological context of Fpr1

• Fpr1 gene deletion failed to modify the pituitary responses to dexamethasone or ANXA1(Ac2-26) [10].
• Studies with peptide antagonists suggest that WKYMVm-NH2 preferentially activates exocytosis via FPRL1 and not FPR, the major receptor for N-formylated peptides such as fMLF [1].
• Surprisingly, a non-desensitizing and non-internalizing mutant of the FPR is unable to initiate apoptosis, indicating that receptor phosphorylation and internalization, but not solely chronic activation due to a lack of desensitization, are critical determinants for the induction of apoptosis by the FPR [11].
• Reconstitution with either arrestin-2 or arrestin-3 is completely sufficient to prevent FPR-mediated apoptosis [11].
• Yet, FPR(+/+) and FPR(-/-) neutrophils showed similar oxidase activation kinetics and G(i) protein-dependent pharmacological sensitivities [12].

Anatomical context of Fpr1

• To identify the TLR4-initiated signaling events that couple to formyl peptide receptor (FPR)1 mRNA stabilization, macrophages were treated with LPS along with a selection of compounds targeting several known signaling pathways [13].
• Signaling in lipopolysaccharide-induced stabilization of formyl Peptide receptor 1 mRNA in mouse peritoneal macrophages [13].
• The N-formyl peptide receptor (FPR) is a seven transmembrane-domain receptor that mediates trafficking and activation of phagocytic leukocytes in response to N-formyl oligopeptides such as fMet-Leu-Phe. cDNAs for high affinity FPRs have been cloned from both human (huFPR) and rabbit (rabFPR) [14].
• The first is murine FPR (muFPR, 76% identical to huFPR) whose gene we have now cloned and expressed in Xenopus oocytes; the second is the previously reported human FPR-like 1 receptor (FPRL1R, 69% identical to huFPR) which was used to construct huFPR-FPRL1R chimeras [14].
• Induction of the Formyl Peptide Receptor 2 in Microglia by IFN-{gamma} and Synergy with CD40 Ligand [6].

Associations of Fpr1 with chemical compounds

• Additionally, a nonselective FPR antagonist (Boc1, 100 microM) overcame the effects of dexamethasone, ANXA1(1-188), ANXA1(Ac2-26), fMLF, and LXA4 on ACTH release, although at a lower concentration (50 microM), it was without effect [10].
• We further demonstrate that this response is not unique to the FPR with numerous additional GPCRs, including the V2 vasopressin, angiotensin II (type 1A), and CXCR2 receptors, capable of initiating apoptosis upon stimulation, whereas GPCRs such as the beta(2)-adrenergic receptor and CXCR4 are not capable of initiating apoptotic signaling [11].
• We found that the formyl peptide receptor agonist formyl-MLF (fMLF) induced anti-nociceptive effects in the formalin test both after the peripheral and central administration [15].
• This less sensitive second pathway may permit continued oxidant generation in response to formyl peptides when FPR is desensitized in high concentrations of the chemotactic gradient [12].
• In FPR-deficient mice, peptide Ac2-26 retained significant inhibitory actions (about 50% of the effects in naive mice), and these were blocked by an FPR antagonist, termed butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe, or Boc2 [16].

Physical interactions of Fpr1

• The cellular effects of PGF(2alpha) are mediated by a G protein-coupled transmembrane receptor designated the FP receptor [17].

Regulatory relationships of Fpr1

• The N-formylpeptide receptor (FPR) and a second G(i)-coupled receptor mediate fMet-Leu-Phe-stimulated activation of NADPH oxidase in murine neutrophils [12].
• We have previously shown that TNF-alpha up-regulated the expression of formyl peptide receptor 2 (mFPR2) in mouse microglial cells, resulting in increased chemotactic responses of such cells to mFPR2 agonists, including amyloid beta1-42 (Abeta42), a critical pathogenic agent in Alzheimer's disease [18].
• IL-4 inhibits expression of the formyl peptide receptor gene in mouse peritoneal macrophages [19].

Other interactions of Fpr1

• IL-4 inhibits the expression of mouse formyl peptide receptor 2, a receptor for amyloid beta1-42, in TNF-alpha-activated microglia [18].
• It is possible that the Hmt gene product is the N-formyl peptide receptor itself and that it represents a class I antigen presentation molecule specialized for binding, transport, and immune presentation of N-formyl-peptide antigens of mitochondrial and prokaryotic origin [20].
• Competition experiments using N-substituted ND1-alpha peptides showed that an N-formyl peptide receptor on the target cell, which differs from the chemotactic peptide receptor, was required for Mta expression [20].
• Both in situ hybridization and beta-galactosidase knocked into the endogenous FP locus were used to determine the cellular distribution of the mouse FP receptor [17].
• On the other hand, i.c. administration of iloprost (an EP1/IP-receptor agonist, 10 fg-100 ng/mouse), butaprost (an EP2-receptor agonist, 10 fg-100 ng/mouse) or prostaglandin F2 alpha (a FP-receptor agonist, 10 fg-100 ng/mouse) 30 min before naloxone (10 mg kg-1, i.p.) did not significantly change the number of jumps precipitated by naloxone [21].

Analytical, diagnostic and therapeutic context of Fpr1

• Expression of the recombinant FPR gene product in FPR-transfected HL60 cells and the absence of the endogenous FPR in vector-transfected HL60 cells was demonstrated by Northern blot and flow cytometric analyses [22].
• The response of the epidermis to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was biphasic in that FP receptor mRNA was increased immediately after treatment, followed by a long-lasting down-regulation at later time points [23].
• 3. Bioassay metabolism studies of bimatoprost and latanoprost (FP receptor agonist prodrug) in the rabbit uterus were conducted using recipient mouse uterus [24].
• We have identified FPR mRNA in the osteoblastic cell lines, Py1a from rats and MC3T3-E1 from mice, as well as in the stem cell cultures, MN-7 and mouse marrow, using reverse transcriptase-polymerase chain reaction technology (RT-PCR) [25].

References