Page last updated: 2024-10-24

thrombin-activated receptor signaling pathway

Definition

Target type: biologicalprocess

A G protein-coupled receptor signaling pathway initiated by thrombin binding to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process. [GOC:mah, PMID:1672265]

Thrombin, a serine protease produced by the coagulation cascade, activates protease-activated receptors (PARs), a family of G protein-coupled receptors, by cleaving their N-terminal extracellular domain. This cleavage exposes a new N-terminus, acting as a tethered ligand that binds to the receptor, triggering intracellular signaling cascades. PARs, particularly PAR1 and PAR4, are key mediators of thrombin signaling in platelets, endothelial cells, and other cell types.

Upon activation, PARs initiate a series of events involving G protein signaling, phospholipase C activation, and calcium mobilization. This leads to the activation of downstream signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway, the phosphoinositide 3-kinase (PI3K) pathway, and the Rho GTPase pathway.

The thrombin-activated receptor signaling pathway plays a crucial role in various physiological processes:

* **Platelet aggregation and hemostasis:** Thrombin activates PARs on platelets, triggering their aggregation and the formation of a platelet plug, essential for hemostasis.
* **Inflammation and vascular permeability:** Thrombin activates PARs on endothelial cells, leading to increased vascular permeability and the recruitment of inflammatory cells.
* **Cell proliferation and migration:** Thrombin-activated receptor signaling contributes to cell proliferation and migration in various cell types, including smooth muscle cells, fibroblasts, and endothelial cells.
* **Wound healing:** Thrombin signaling promotes wound healing by stimulating angiogenesis, cell migration, and extracellular matrix deposition.

Dysregulation of thrombin-activated receptor signaling can contribute to pathological conditions, including thrombosis, atherosclerosis, and inflammation. This pathway is a target for therapeutic interventions, with PAR inhibitors showing potential for treating various cardiovascular diseases and inflammatory disorders.'
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Proteins (4)

ProteinDefinitionTaxonomy
Proteinase-activated receptor 4A proteinase-activated receptor 4 that is encoded in the genome of human. [PRO:WCB, UniProtKB:Q96RI0]Homo sapiens (human)
Proteinase-activated receptor 2A proteinase-activated receptor 2 that is encoded in the genome of human. [PRO:WCB, UniProtKB:P55085]Homo sapiens (human)
Proteinase-activated receptor 1A proteinase-activated receptor 1 that is encoded in the genome of human. [PRO:WCB, UniProtKB:P25116]Homo sapiens (human)
15-hydroxyprostaglandin dehydrogenase [NAD(+)]A 15-hydroxyprostaglandin dehydrogenase [NAD(+)] that is encoded in the genome of human. [PRO:DNx, UniProtKB:P15428]Homo sapiens (human)

Compounds (23)

CompoundDefinitionClassesRoles
ciglitazoneciglitazone : An aromatic ether that consists of 1,3-thiazolidine-2,4-dione with position 5 substituted by a 4-[(1-methylcyclohexyl)methoxy]benzyl group. A selective PPARgamma agonist.

ciglitazone: structure given in second source; PPAR agonist used for type II diabetes
aromatic ether;
thiazolidinone
antineoplastic agent;
insulin-sensitizing drug
2-(4-morpholinyl)-8-phenyl-4h-1-benzopyran-4-one2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one: specific inhibitor of phosphatidylinositol 3-kinase; structure in first sourcechromones;
morpholines;
organochlorine compound
autophagy inhibitor;
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor;
geroprotector
ultram2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol : A tertiary alcohol that is cyclohexanol substituted at positions 1 and 2 by 3-methoxyphenyl and dimethylaminomethyl groups respectively.aromatic ether;
tertiary alcohol;
tertiary amino compound
triptolidediterpenoid;
epoxide;
gamma-lactam;
organic heteroheptacyclic compound
antispermatogenic agent;
plant metabolite
omega-n-methylarginineN(omega)-methyl-L-arginine : A L-arginine derivative with a N(omega)-methyl substituent.

omega-N-Methylarginine: A competitive inhibitor of nitric oxide synthetase.
amino acid zwitterion;
arginine derivative;
guanidines;
L-arginine derivative;
non-proteinogenic L-alpha-amino acid
bdp 121-(quinoxalin-6-ylcarbonyl)piperidine: modulates AMPA receptor desensitization ; an analog of 1-(1,3-benzodioxol-5-ylcarbonyl)piperidineN-acylpiperidine
vu0099704VU0099704: an antagonist of protease activated receptor 4 (PAR-4); structure in first source
2-bromo-N-[3-(1-oxopropylamino)phenyl]benzamidebenzamides
2-bromo-N-[3-(1-oxobutylamino)phenyl]benzamidebenzamides
3-(2,5-dimethyl-1-phenyl-3-pyrrolyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepinepyrroles
[1-(3-methylphenyl)-5-benzimidazolyl]-(1-piperidinyl)methanonebenzimidazoles
sw033291SW033291: inhibits 15-hydroxyprostaglandin dehydrogenase (15-PGDH)
sch 79797quinazolines
morphineMeconium: The thick green-to-black mucilaginous material found in the intestines of a full-term fetus. It consists of secretions of the INTESTINAL GLANDS; BILE PIGMENTS; FATTY ACIDS; AMNIOTIC FLUID; and intrauterine debris. It constitutes the first stools passed by a newborn.morphinane alkaloid;
organic heteropentacyclic compound;
tertiary amino compound
anaesthetic;
drug allergen;
environmental contaminant;
geroprotector;
mu-opioid receptor agonist;
opioid analgesic;
plant metabolite;
vasodilator agent;
xenobiotic
seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamideseryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide: a proteinase-activated receptor-2-activating peptide; SL-NH2 is NOT Ser-Leu-NH2 here
tapentadolTapentadol: An opioid analgesic, MU OPIOID RECEPTOR agonist, and noradrenaline reuptake inhibitor that is used in the treatment of moderate to severe pain, and of pain associated with DIABETIC NEUROPATHIES.alkylbenzene
o-demethyltramadolalkylbenzene;
ring assembly
rwj-56110RWJ-56110: a PAR-1 antagonist; structure in first source
vorapaxarvorapaxar : A carbamate ester that is the ethyl ester of [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethynyl}-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl]carbamic acid. A protease-activated receptor-1 antagonist used (as its sulfate salt) for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease. It has been shown to reduce the rate of a combined endpoint of cardiovascular death, MI, stroke and urgent coronary revascularisation.

vorapaxar: has antiplatelet activity; structure in first source
carbamate ester;
lactone;
naphthofuran;
organofluorine compound;
pyridines
cardiovascular drug;
platelet aggregation inhibitor;
protease-activated receptor-1 antagonist
2-furoyl-ligrlo-amide2-furoyl-LIGRLO-amide: a potent and selective proteinase-activated receptor 2 agonist
e 5555E 5555: a 2-iminopyridine derivative and platelet aggregation inhibitoraromatic ketone
zstk474ZSTK-474 : A triamino-1,3,5-triazine that is 1,3,5-triazine in which two of the hydrogens have been replaced by morpholin-4-yl groups while the third hydrogen has been replaced by a 2-(difluoromethyl)benzimidazol-1-yl group. It is an inhibitor of phosphatidylinositol 3-kinase.benzimidazoles;
morpholines;
organofluorine compound;
triamino-1,3,5-triazine
antineoplastic agent;
EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor
AZ3451benzimidazoles;
benzodioxoles;
nitrile;
organobromine compound;
secondary carboxamide
anti-inflammatory agent;
autophagy inducer;
PAR2 negative allosteric modulator