Nomenclature: FPR1

Family: Formylpeptide receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 350 19q13.4 FPR1 formyl peptide receptor 1 3,57
Mouse 7 364 17 A3.2 Fpr1 formyl peptide receptor 1 23
Rat 7 355 1q12 Fpr1 formyl peptide receptor 1 55
Previous and Unofficial Names
FMLP
NFPR
FMLPR
Formyl peptide
fMLP
FPR
Fpr1_predicted
LOC292409
fMet-Leu-Phe receptor
formyl peptide receptor 1
formyl peptide receptor 1 (predicted)
fMLF-R
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniProtKB
Wikipedia
Natural/Endogenous Ligands
annexin I {Sp: Human} , annexin I {Sp: Mouse} , annexin I {Sp: Rat}
cathepsin G {Sp: Human} , cathepsin G {Sp: Mouse} , cathepsin G {Sp: Rat}
Rank order of potency (Human)
fMet-Leu-Phe > cathepsin G (CTSG, P08311) > annexin I (ANXA1, P04083)  [45,79]
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
fMet-Leu-Phe-Ile-Ile-Lys-FITC Mm Full agonist 8.6 pKd 32
pKd 8.6 [32]
[3H]fMet-Leu-Phe Hs Full agonist 7.6 – 9.3 pKd 39
pKd 7.6 – 9.3 (Kd 5x10-10 – 2.51x10-8 M) [39]
[125I]cathepsin G (human) Hs Full agonist 7.0 pKd 79
pKd 7.0 [79]
fMet-Ile-Val-Thr-Leu-Phe Mm Full agonist 10.7 pEC50 32
pEC50 10.7 [32]
fMet-Ile-Phe-Leu Hs Full agonist 10.5 pEC50 67
pEC50 10.5 [67]
fMet-Leu-Phe Hs Full agonist 10.1 – 10.2 pEC50 22,76
pEC50 10.1 – 10.2 [22,76]
fMet-Met-Tyr-Ala-Leu-Phe Mm Full agonist 10.0 pEC50 32
pEC50 10.0 [32]
fMet-Ile-Phe-Leu Mm Full agonist 9.5 pEC50 32
pEC50 9.5 [32]
WKYMVm Hs Full agonist 9.0 pEC50 42
pEC50 9.0 [42]
WKYMVm Mm Full agonist 9.0 pEC50 32-33
pEC50 9.0 [32-33]
Met-Met-Trp-Leu-Leu Hs Full agonist 9.0 pEC50 12
pEC50 9.0 [12]
fMet-Met-Trp-Leu-Leu Hs Full agonist 9.0 pEC50 12
pEC50 9.0 [12]
fMet-Ile-Val-Ile-Leu Hs Full agonist 8.7 pEC50 66
pEC50 8.7 [66]
pyrazolone, 1 Mm Full agonist 8.7 pEC50 32
pEC50 8.7 [32]
fMet-Ile-Val-Thr-Leu-Phe Hs Full agonist 8.6 pEC50 66
pEC50 8.6 [66]
T20(DP178) Hs Full agonist 8.3 pEC50 31,78
pEC50 8.3 [31,78]
fMet-Leu-Phe-Glu Mm Full agonist 8.2 pEC50 32
pEC50 8.2 [32]
fMet-Met-Tyr-Ala-Leu-Phe Hs Full agonist 8.0 pEC50 66
pEC50 8.0 [66]
AG-14 Hs Full agonist 7.4 pEC50 69
pEC50 7.4 [69]
annexin I {Sp: Human} Mm Full agonist 6.6 pEC50 17,63
pEC50 6.6 [17,63]
gG-2p20 Hs Full agonist 6.2 – 6.3 pEC50 5
pEC50 6.2 – 6.3 [5]
R-(-)-6-methyl-2,4-disubstituted pyridazin-3(2H)-one Hs Full agonist 6.0 pEC50 15
pEC50 6.0 [15]
annexin I-(2-26) {Sp: Human} Hs Full agonist 5.8 – 6.1 pEC50 26,82
pEC50 5.8 – 6.1 [26,82]
AG-09/1 Hs Full agonist 5.6 pEC50 38
pEC50 5.6 [38]
AG-11/03 Hs Full agonist 5.6 pEC50 37
pEC50 5.6 [37]
fMet-Leu-Phe Mm Full agonist 4.7 pEC50 30,77
pEC50 4.7 [30,77]
spinorphin Mm Partial agonist 3.9 pEC50 47
pEC50 3.9 [47]
View species-specific agonist tables
Agonist Comments
FPR1-mediated neutrophil functions have different requirements for agonist concentrations, from low (chemotaxis) to high (superoxide generation). Some early studies of fMet-Leu-Phe were conducted on rabbit neutrophils [9,23]. The annexin I peptides include Ac2-12, Ac2-26 and Ac9-25. These peptides bind to both FPR1 and FPR2 with similar affinities, and therefore non-selective according to IUPHAR standard [17,26,36,82]. T20/DP178, an ectodomain peptide of human immunodeficiency virus type 1 gp41, is an activator of FPR1 [78]. AG-14 (1,3-benzodioxolane-5-carboxylic acid 4`-benzyloxy-3`-methoxybenzylidene-hydrazide) represents a novel small-molecule agonist of FPR1. Selected chiral compounds are potent mixed FPR1/FPR2 agonists, among which R-(-)-forms generally exhibits higher activity than the S-(+)-enantiomers [15]. Benzimidazole derivatives include 2-(benzimidazol-2-ylthio)-N-phenylacetamide-derivatives and 2-(5-alkoxybenzimidazol-2-ylthio)-N-phenylacetamide derivatives, among which FPR1-specific agonists are AG-09/1, AG-09/2, AG-09/13, AG-09/18, AG-09/19, AG-09/21, AG-11/03, AG-11/05 and AG-11/23, while the other compounds tested in the series are mixed FPR1/FPR2 agonists or FPR2-specific agonists [37-38]. Despite acting as a calcium-mobilizing agonist at mouse Fpr1, spinorphin is a weak chemotactic agonist and effectively blocks neutrophil chemotaxis induced by fMLF at concentrations selective for mouse Fpr1 [47].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[125I]CHIPS Hs Antagonist 7.5 pKd 29
pKd 7.5 [29]
3570-0208 [PMID:19807662] Hs Antagonist 7.0 pKi 2
pKi 7.0 [2]
cyclosporin H Hs Antagonist 6.1 – 7.1 pKi 84,87
pKi 6.1 – 7.1 [84,87]
t-Boc-FLFLF Hs Antagonist 6.0 – 6.5 pKi 84
pKi 6.0 – 6.5 [84]
deoxycholic acid Hs Antagonist 4.0 pKi 13
pKi 4.0 [13]
chenodeoxycholic acid Hs Antagonist 4.0 pKi 14
pKi 4.0 [14]
cyclosporin A Hs Antagonist 6.2 – 6.3 pEC50 86
pEC50 6.2 – 6.3 [86]
BVT173187 Hs Antagonist 7.0 pIC50 11
pIC50 7.0 [11]
t-Boc-FLFLF Hs Antagonist 6.6 pIC50 83
pIC50 6.6 [83]
i-Boc-Met-Leu-Phe Hs Antagonist 6.6 pIC50 18
pIC50 6.6 [18]
diamide 7 Hs Antagonist 6.5 pIC50 81
pIC50 6.5 [81]
methionine benzimidazole 6 Hs Antagonist 6.3 pIC50 81
pIC50 6.3 [81]
t-Boc-Met-Leu-Phe Hs Antagonist 6.2 pIC50 83
pIC50 6.2 [83]
group E 1682-2106 [PMID:16118363] Hs Antagonist 5.3 pIC50 20
pIC50 5.3 [20]
sufinpyrazone Hs Antagonist 5.0 pIC50 88
pIC50 5.0 [88]
spinorphin Hs Antagonist 4.3 pIC50 47,57
pIC50 4.3 [47,57]
Antagonist Comments
CHIPS is a 14.1 kDa protein found in more than half of the clinical strains of Staphylococcus aureus. Its N-terminal peptides of various lengths are also FPR1 antagonists but are 3 orders of magnitude less potent [29]. Boc-Met-Leu-Phe is also termed Boc1, and Boc-Phe-Leu-Phe-Leu-Phe is referred to as Boc2. The latter is an antagonist of both FPR1 and FPR2, and therefore is considered non-selective. Spinorphin is an endogenous peptide with the sequence of Leu-Val-Val-Tyr-Pro-Trp-Thr. BVT173187 (3,5-dichloro-N-(2-chloro-5-methyl-phenyl)-2-hydroxy-benzamide) fulfills the criteria for an FPR1 inhibitor selective for FPR1 over FPR2, and the potency is the same as that of cyclosporine H, but signaling through C5aR and CXCR (recognizing IL8) is also affected by BVT173187.
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Phospholipase C stimulation
Phospholipase A2 stimulation
Phospholipase D stimulation
References:  1,27,56,74
Secondary Transduction Mechanisms
Transducer Effector/Response
Calcium channel
Comments:  Increase of intracellular Ca2+ level results in opening of membrane Ca2+ channel in fMLF-stimulated cells. This response is secondary to release of Ca2+ from intracelluar stores.
References:  49,58,62,65
Tissue Distribution
Non-myeloid cells: Low levels of FPR1 transcript and protein are found in hepatocytes, platelets, endothelial cells, astrocytes, microglial cells, vascular smooth muscle cells, and fibroblasts. Using a polyclonal Ab, FPR1 expression is detected in thyroid, adrenal, motor and sensory neurons, cerebellar systems, and colon.
Species:  Human
Technique:  Immunocytochemistry
References:  4,16,41,43,53
Myeloid cells: FPR1 is primarily expressed in neutrophils, monocytes and macrophages. It is also found in eosinophils and basophils. FPR1 is not found on myeloblast cell surface but emerges gradually through stages of neutrophil maturation. Promyelocytic leukemia cell lines such as HL-60 may be differentiated to induce FPR1 expression. There is an intracellular pool of FPR1 in neutrophil granules that can be mobilized for cell surface expression.
Species:  Human
Technique:  Radioligand binding
References:  71,76,85,89
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Agonist-induced incorporation of non-hydrolyzable GTP analogs. This assay reflects activation of the receptor-coupled Gi protien, and can be blocked by pertussis toxin treatment of the cells
Species:  Human
Tissue:  Neutrophils, FPR1-expressing cell lines
Response measured:  Increase of [35S]-GTPγS in precipitated Gi protein
References:  8,72
Activation of PLA2, resulting in the generation of arachidonic acid.
Species:  Human
Tissue:  neutrophils
Response measured:  Arachidonic acid release
References:  8,52
Agonist-induced phosphoinositide metabolism. This assay reflects FPR1-mediated PLCbeta activation, which is downstream of Gi protein activation. The activation of PLCbeta is mediated by Gbeta/gamma subunits.
Species:  Human
Tissue:  Neutrophils, leukemia cell lines expressing FPR1
Response measured:  PIP2 hydrolysis
References:  40,75,80
Activation of PLD and formation of phosphatidate
Species:  Human
Tissue:  Neutrophils
Response measured:  [3H]glycerol-labeled phosphatidate formation
References:  7,46,61
Ca2+ mobilization. This function is induced when FPR1 is activated by agonists. The rise of intracellular Ca2+ consists of release of Ca2+ from intracellular stores and Ca2+ influx. The function is secondary to PLCbeta activation and IP3 production, and be reproduced in various cells.
Species:  Human
Tissue:  Neutrophils and various transfected cells
Response measured:  Intracellular Ca2+ concentration
References:  49,58,62,65
Physiological Functions
Degranulation. Release of lysosozyme and beta-glucuronidase has been used in early studies of FPR1 activation. This function is reproducible with exogenously expressed FPR1.
Species:  Human
Tissue:  neutrophils
References:  6,76
Adhesion. Formylpeptides such as fMLF increase neutrophil adhesion to coated surface, believed to result from increased integrin activities.
Species:  Human
Tissue:  Myeloid cells, neutrophils
References:  10,34,54
One study indicates that fMLF has anti-nociceptive effect in mouse formalin test of nociceptive stimulation. Some of the Annexin I peptides also reduced nociceptive response.
Species:  Mouse
Tissue:  Whole animal
References:  64
Chemotaxis: Formylpeptides stimulate chemotaxis of phagocytes at low concentrations . This function is confirmed using exogenously expressed FPR1. Chemotaxis is responsible for neutrophil accumulation at sites of acute bacterial infection.
Species:  Human
Tissue:  Neutrophils from human and rabbits.
References:  22,70,76,89
Physiological Consequences of Altering Gene Expression
Silencing of the human FPR1 gene by siRNA leads to impaired chemotaxis and calcium mobilization in transfected cells, and reduced superoxide secretion in macrophages, when challenged with fMLF.
Species:  Human
Tissue:  Glioma cell line
Technique:  RNAi
References:  44
Deletion of the mouse FPR1 gene results in compromised immunity to Listeria monocytogenes infection, manifested as reduced ability of bacteria clearance and increased mortality rate. Neutrophils from the knockout mice respond poorly to fMLF.
Species:  Mouse
Tissue:  Neutrophils
Technique:  Gene targeting in embryonic stem cells
References:  24
Fpr1 (-/-) mice exhibits increased exploratory activity, reduced anxiety-like behaviour, and impaired fear memory, but normal spatial memory and learning capacity.
Species:  Mouse
Tissue:  Brain
Technique:  Gene targeting in embryonic stem cells
References:  25
Deficiency in mFpr1 and mFpr2 exacerbated the severity of the infection and increased the mortality of infected mice. The mechanism involved impaired early neutrophil recruitment to the liver with Fpr1 and Fpr2 being sole receptors for neutrophils to sense Listeria chemoattractant signals and for production of bactericidal superoxide.
Species:  Mouse
Tissue:  Neutrophils
Technique:  Gene targeting in embryonic stem cells
References:  48
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Fpr1tm1Gao Fpr1tm1Gao/Fpr1tm1Gao
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:107443  MP:0002419 abnormal innate immunity PMID: 9989980 
Fpr1tm1Gao Fpr1tm1Gao/Fpr1tm1Gao
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:107443  MP:0008720 impaired neutrophil migration PMID: 9989980 
Fpr1tm1Gao Fpr1tm1Gao/Fpr1tm1Gao
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:107443  MP:0002412 increased susceptibility to bacterial infection PMID: 9989980 
Fpr1tm1Gao Fpr1tm1Gao/Fpr1tm1Gao
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:107443  MP:0009788 increased susceptibility to bacterial infection induced morbidity/mortality PMID: 9989980 
Biologically Significant Variants
Type:  Single nucleotide polymorphism
Species:  Human
Description:  Single nucleotide polymorphisms (SNPs) have been identified in the FPR1 gene. These SNPs result in FPR variants with the following changes: I11T, V101L, R190W, N192K, A346E. Genetic analysis showed association of the N192K and R190W with the risk of having aggressive periodontitis.
References:  19,50,68
Type:  Single nucleotide polymorphism
Species:  Human
Description:  It was reported that juvenile periodontitis patients, whose neutrophils respond poorly to fMLF, carry SNPs that cause changes in F110(S) and C126W. Test of the FPR1 variants in transfected cells found defective chemotaxis and degranulation in response to fMLF, but normal cell surface expression. However, the accuracy of the original SNP study could not be confirmed.
References:  19,28,35,59,73
Type:  Single nucleotide polymorphism
Species:  Human
Description:  FPR1 C32T SNP interacts with age, is associated with higher and a 5 years increase of BP levels in healthy individuals aged less than 45 years.
References:  21
Type:  Single nucleotide polymorphism
Species:  Human
Description:  The relatively rare 348T/T genotype is associated with significantly impaired PMN chemotaxis and an increased risk for developing aggressive periodontitis in African Americans.
References:  51
Type:  Single nucleotide polymorphism
Species:  Human
Description:  The Asp192Lys polymorphism in FPR1 is significantly associated with increased susceptibility to stomach cancer among the elderly Japanese population.
References:  60
Available Assays
DiscoveRx PathHunter® CHO-K1 FPR1 β-Arrestin Cell Line (Cat no. 93-0314C2)
PathHunter® eXpress FPR1 CHO-K1 β-Arrestin GPCR Assay (Cat no. 93-0314E2CP0M)
more info

REFERENCES

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Formylpeptide receptors: FPR1. Last modified on 16/09/2013. Accessed on 20/10/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=222.

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