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PAR4

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Target not currently curated in GtoImmuPdb

Target id: 350

Nomenclature: PAR4

Family: Proteinase-activated receptors

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 385 19p13.11 F2RL3 F2R like thrombin or trypsin receptor 3
Mouse 7 396 8 B3.3 F2rl3 coagulation factor II (thrombin) receptor-like 3
Rat 7 395 16p14 F2rl3 F2R like thrombin or trypsin receptor 3
Previous and Unofficial Names Click here for help
coagulation factor II receptor-like 3 | protease-activated receptor 4 | thrombin receptor-like 3 | coagulation factor II (thrombin) receptor-like 3 | F2R like thrombin/trypsin receptor 3
Database Links Click here for help
Specialist databases
GPCRdb par4_human (Hs), par4_mouse (Mm), par4_rat (Rn)
Other databases
Alphafold Q96RI0 (Hs), O88634 (Mm), Q920E0 (Rn)
ChEMBL Target CHEMBL4691 (Hs)
Ensembl Gene ENSG00000127533 (Hs), ENSMUSG00000050147 (Mm), ENSRNOG00000068093 (Rn)
Entrez Gene 9002 (Hs), 14065 (Mm), 116498 (Rn)
Human Protein Atlas ENSG00000127533 (Hs)
KEGG Gene hsa:9002 (Hs), mmu:14065 (Mm), rno:116498 (Rn)
OMIM 602779 (Hs)
Pharos Q96RI0 (Hs)
RefSeq Nucleotide NM_003950 (Hs), NM_007975 (Mm), NM_053808 (Rn)
RefSeq Protein NP_003941 (Hs), NP_032001 (Mm), NP_446260 (Rn)
UniProtKB Q96RI0 (Hs), O88634 (Mm), Q920E0 (Rn)
Wikipedia F2RL3 (Hs)
Natural/Endogenous Ligands Click here for help
cathepsin G {Sp: Human} , cathepsin G {Sp: Mouse} , cathepsin G {Sp: Rat}
thrombin {Sp: Human} , thrombin {Sp: Mouse} , thrombin {Sp: Rat}
serine proteases
Agonist proteases (Human)
thrombin (F2, P00734), trypsin, cathepsin G (CTSG, P08311)

Download all structure-activity data for this target as a CSV file go icon to follow link

Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
BMS-986120 Small molecule or natural product Hs Antagonist 10.0 pKd 10,14
⤷ pKd 10.0 (Kd 9.8x10-11 M) [10,14]
BMS-986141 Small molecule or natural product Hs Antagonist 10.0 pKd 10
⤷ pKd 10.0 (Kd 1x10-10 M) [10]
Description: Affinity determined by saturation binding assay.
UDM-001651 Small molecule or natural product Hs Antagonist 8.6 pIC50 8
⤷ pIC50 8.6 (IC50 2.4x10-9 M) [8]
Description: Measuring inhibition of PAR4 agonist-induced intracellular calcium mobilization in HEK293-PAR4 cells by FLIPR assay.
YD-3 Small molecule or natural product Hs Antagonist 6.9 pIC50 13
⤷ pIC50 6.9 (IC50 1.3x10-7 M) [13]
Description: Antagonism of PAR4-AP-stimulated human platelet aggregation.
ML354 Small molecule or natural product Hs Antagonist 6.8 pIC50 13
⤷ pIC50 6.8 (IC50 1.4x10-7 M) [13]
Description: Antagonism measured in a novel PAC-1 fluorescent αIIbβ3 activation assay.
P4pal-10 Peptide Hs Antagonist - - 2
⤷ [2]
RAG8 Peptide Hs Antagonist - - 11
⤷ [11]
Expression Datasets Click here for help

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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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Physiological Consequences of Altering Gene Expression Click here for help
PAR4-deficiency reduces hepatocellular necrosis. PAR4-deficient mice show reduced progression of ANIT-induced cholestatic liver injury.
Species:  Mouse
Tissue:  Liver
Technique:  Gene knockouts
References:  6
PAR4-deficiency attenuates cerebral ischemia and reperfusion injury. PAR4 knockout mice have lower cerebral infarct volume, improved neurologic and motor function, and reduction of blood brain barrier disruption and cerebral edema.
Species:  Mouse
Tissue:  Brain
Technique:  Gene knockouts
References:  7
PAR4-deficient mice are protected against thrombosis.
Species:  Mouse
Tissue:  Platelets
Technique:  Gene knockouts
References:  1,4-5,12
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
F2rtm1Ajc|F2rl1tm1Cgh|F2rl3tm1Cgh F2rtm1Ajc/F2rtm1Ajc,F2rl1tm1Cgh/F2rl1tm1Cgh,F2rl3tm1Cgh/F2rl3tm1Cgh
involves: 129S4/SvJae * C57BL/6		 MGI:101802  MGI:101910  MGI:1298207  MP:0008762 embryonic lethality PMID: 16434493 
F2rl3tm1.1Cgh F2rl3tm1.1Cgh/F2rl3tm1.1Cgh
involves: 129S4/SvJae * C57BL/6		 MGI:1298207  MP:0005606 increased bleeding time PMID: 12384423 
F2rl3tm1.1Cgh F2rl3tm1.1Cgh/F2rl3tm1.1Cgh
involves: 129S4/SvJae * C57BL/6		 MGI:1298207  MP:0005048 thrombosis PMID: 12384423 
Biologically Significant Variants Click here for help
Type:  Single nucleotide polymorphism
Species:  Human
Description:  The Ala120 -> Thr variant is associated with higher PAR4-induced platelet aggregation and calcium flux.
Amino acid change:  A120T
Amino acids:  385
SNP accession:  rs773902, VAR_028300
References:  3
Type:  Single nucleotide polymorphism
Species:  Human
Description:  rs773857 risk allele (c.4003-925G>A) homozygotes have significantly increased platelet counts and increased platelet reactivity.
Amino acid change:  G>A
Nucleotide change:  925G>A
SNP accession:  rs773857
References:  9

References

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1. Cornelissen I, Palmer D, David T, Wilsbacher L, Concengco C, Conley P, Pandey A, Coughlin SR. (2010) Roles and interactions among protease-activated receptors and P2ry12 in hemostasis and thrombosis. Proc Natl Acad Sci USA, 107 (43): 18605-10. [PMID:20930120]

2. Covic L, Misra M, Badar J, Singh C, Kuliopulos A. (2002) Pepducin-based intervention of thrombin-receptor signaling and systemic platelet activation. Nat Med, 8 (10): 1161-5. [PMID:12357249]

3. Edelstein LC, Simon LM, Lindsay CR, Kong X, Teruel-Montoya R, Tourdot BE, Chen ES, Ma L, Coughlin S, Nieman M et al.. (2014) Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race. Blood, 124 (23): 3450-8. [PMID:25293779]

4. Hamilton JR, Cornelissen I, Coughlin SR. (2004) Impaired hemostasis and protection against thrombosis in protease-activated receptor 4-deficient mice is due to lack of thrombin signaling in platelets. J Thromb Haemost, 2 (8): 1429-35. [PMID:15304051]

5. Lee H, Sturgeon SA, Jackson SP, Hamilton JR. (2012) The contribution of thrombin-induced platelet activation to thrombus growth is diminished under pathological blood shear conditions. Thromb Haemost, 107 (2): 328-37. [PMID:22187047]

6. Luyendyk JP, Mackman N, Sullivan BP. (2011) Role of fibrinogen and protease-activated receptors in acute xenobiotic-induced cholestatic liver injury. Toxicol Sci, 119 (1): 233-43. [PMID:20974703]

7. Mao Y, Zhang M, Tuma RF, Kunapuli SP. (2010) Deficiency of PAR4 attenuates cerebral ischemia/reperfusion injury in mice. J Cereb Blood Flow Metab, 30 (5): 1044-52. [PMID:20087365]

8. Miller MM, Banville J, Friends TJ, Gagnon M, Hangeland JJ, Lavallée JF, Martel A, O'Grady H, Rémillard R, Ruediger E et al.. (2019) Discovery of Potent Protease-Activated Receptor 4 Antagonists with in Vivo Antithrombotic Efficacy. J Med Chem, 62 (16): 7400-7416. [PMID:31246024]

9. Muehlschlegel JD, Perry TE, Liu KY, Fox AA, Smith SA, Lichtner P, Collard CD, Shernan SK, Hartwig JH, Body SC et al.. (2012) Polymorphism in the protease-activated receptor-4 gene region associates with platelet activation and perioperative myocardial injury. Am J Hematol, 87 (2): 161-6. [PMID:22228373]

10. Priestley ES, Banville J, Deon D, Dubé L, Gagnon M, Guy J, Lapointe P, Lavallée JF, Martel A, Plamondon S et al.. (2022) Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4. J Med Chem, [Epub ahead of print]. DOI: 10.1021/acs.jmedchem.2c00359 [PMID:35729784]

11. Ramachandran R, Mihara K, Thibeault P, Vanderboor CM, Petri B, Saifeddine M, Bouvier M, Hollenberg MD. (2017) Targeting a Proteinase-Activated Receptor 4 (PAR4) Carboxyl Terminal Motif to Regulate Platelet Function. Mol Pharmacol, 91 (4): 287-295. [PMID:28126849]

12. Sambrano GR, Weiss EJ, Zheng YW, Huang W, Coughlin SR. (2001) Role of thrombin signalling in platelets in haemostasis and thrombosis. Nature, 413 (6851): 74-8. [PMID:11544528]

13. Wen W, Young SE, Duvernay MT, Schulte ML, Nance KD, Melancon BJ, Engers J, Locuson 2nd CW, Wood MR, Daniels JS et al.. (2014) Substituted indoles as selective protease activated receptor 4 (PAR-4) antagonists: Discovery and SAR of ML354. Bioorg Med Chem Lett, 24 (19): 4708-13. [PMID:25176330]

14. Wong PC, Seiffert D, Bird JE, Watson CA, Bostwick JS, Giancarli M, Allegretto N, Hua J, Harden D, Guay J et al.. (2017) Blockade of protease-activated receptor-4 (PAR4) provides robust antithrombotic activity with low bleeding. Sci Transl Med, 9 (371). [PMID:28053157]

Contributors

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