PAR4 | Proteinase-activated receptors | IUPHAR/BPS Guide to PHARMACOLOGY

PAR4

Target id: 350

Nomenclature: PAR4

Family: Proteinase-activated receptors

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for PAR4 in GtoImmuPdb

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 385 19p12 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 16 F2rl3 F2R like thrombin or trypsin receptor 3
Previous and Unofficial Names
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
Specialist databases
GPCRDB par4_human (Hs), par4_mouse (Mm), par4_rat (Rn)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
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

Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
YD-3 Hs Antagonist 6.9 pIC50 9
pIC50 6.9 (IC50 1.3x10-7 M) [9]
Description: Antagonism of PAR4-AP-stimulated human platelet aggregation.
ML354 Hs Antagonist 6.8 pIC50 9
pIC50 6.8 (IC50 1.4x10-7 M) [9]
Description: Antagonism measured in a novel PAC-1 fluorescent αIIbβ3 activation assay.
Expression Datasets

Show »

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]

There should be a chart of expression data here, you may need to enable JavaScript!
Physiological Consequences of Altering Gene Expression
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:  5
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:  6
PAR4-deficient mice are protected against thrombosis.
Species:  Mouse
Tissue:  Platelets
Technique:  Gene knockouts
References:  1,3-4,8
Phenotypes, Alleles and Disease Models Mouse data from MGI

Show »

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
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: 
References:  2
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: 
References:  7

References

Show »

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. U.S.A., 107 (43): 18605-10. [PMID:20930120]

2. 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]

3. 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]

4. 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]

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

Contributors

Show »

How to cite this page

Nigel Bunnett, Kathryn DeFea, Justin Hamilton, Morley D. Hollenberg, Rithwik Ramachandran, JoAnn Trejo.
Proteinase-activated receptors: PAR4. Last modified on 20/02/2017. Accessed on 15/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=350.