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)
| Protein | Definition | Taxonomy |
|---|---|---|
| Proteinase-activated receptor 4 | A proteinase-activated receptor 4 that is encoded in the genome of human. [PRO:WCB, UniProtKB:Q96RI0] | Homo sapiens (human) |
| Proteinase-activated receptor 2 | A proteinase-activated receptor 2 that is encoded in the genome of human. [PRO:WCB, UniProtKB:P55085] | Homo sapiens (human) |
| Proteinase-activated receptor 1 | A 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)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| ciglitazone | ciglitazone : 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-one | 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one: specific inhibitor of phosphatidylinositol 3-kinase; structure in first source | chromones; morpholines; organochlorine compound | autophagy inhibitor; EC 2.7.1.137 (phosphatidylinositol 3-kinase) inhibitor; geroprotector |
| ultram | 2-[(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 | |
| triptolide | diterpenoid; epoxide; gamma-lactam; organic heteroheptacyclic compound | antispermatogenic agent; plant metabolite | |
| omega-n-methylarginine | N(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 12 | 1-(quinoxalin-6-ylcarbonyl)piperidine: modulates AMPA receptor desensitization ; an analog of 1-(1,3-benzodioxol-5-ylcarbonyl)piperidine | N-acylpiperidine | |
| vu0099704 | VU0099704: an antagonist of protease activated receptor 4 (PAR-4); structure in first source | ||
| 2-bromo-N-[3-(1-oxopropylamino)phenyl]benzamide | benzamides | ||
| 2-bromo-N-[3-(1-oxobutylamino)phenyl]benzamide | benzamides | ||
| 3-(2,5-dimethyl-1-phenyl-3-pyrrolyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine | pyrroles | ||
| [1-(3-methylphenyl)-5-benzimidazolyl]-(1-piperidinyl)methanone | benzimidazoles | ||
| sw033291 | SW033291: inhibits 15-hydroxyprostaglandin dehydrogenase (15-PGDH) | ||
| sch 79797 | quinazolines | ||
| morphine | Meconium: 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-leucinamide | seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide: a proteinase-activated receptor-2-activating peptide; SL-NH2 is NOT Ser-Leu-NH2 here | ||
| tapentadol | Tapentadol: 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-demethyltramadol | alkylbenzene; ring assembly | ||
| rwj-56110 | RWJ-56110: a PAR-1 antagonist; structure in first source | ||
| vorapaxar | vorapaxar : 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-amide | 2-furoyl-LIGRLO-amide: a potent and selective proteinase-activated receptor 2 agonist | ||
| e 5555 | E 5555: a 2-iminopyridine derivative and platelet aggregation inhibitor | aromatic ketone | |
| zstk474 | ZSTK-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 |
| AZ3451 | benzimidazoles; benzodioxoles; nitrile; organobromine compound; secondary carboxamide | anti-inflammatory agent; autophagy inducer; PAR2 negative allosteric modulator |