Target type: molecularfunction
A G protein-coupled receptor activity that is activated by cleavage by thrombin, which exposes a tethered ligand corresponding to the new N-terminus, which binds to the receptor and activates it. [GOC:ai, GOC:pg, PMID:20423334]
Thrombin-activated receptor (PAR) activity involves a complex cascade of molecular events that ultimately lead to cellular signaling and various physiological responses. PARs are G protein-coupled receptors (GPCRs) that are activated by proteolytic cleavage of their N-terminal extracellular domain. Thrombin, a serine protease, is a key activator of PARs, particularly PAR1 and PAR4.
Upon thrombin cleavage, the newly exposed N-terminus of the PAR acts as a tethered ligand, binding to the receptor's extracellular domain and initiating signaling. This interaction triggers a conformational change in the receptor, leading to the activation of intracellular signaling pathways.
The activation of PARs by thrombin can initiate a variety of downstream events, including:
- **G protein activation:** PARs couple to heterotrimeric G proteins, primarily Gq and Gi. The activation of Gq leads to the activation of phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 promotes calcium release from intracellular stores, while DAG activates protein kinase C (PKC).
- **MAP kinase signaling:** PAR activation can activate the mitogen-activated protein kinase (MAPK) signaling pathway, leading to the phosphorylation of various downstream targets involved in cell proliferation, differentiation, and survival.
- **Calcium signaling:** The release of calcium from intracellular stores, triggered by IP3, plays a critical role in a wide range of cellular processes, including muscle contraction, secretion, and gene expression.
- **Cytoskeletal rearrangement:** PAR activation can induce changes in the cytoskeleton, leading to cell migration, adhesion, and wound healing.
- **Transcriptional regulation:** PARs can regulate gene expression by influencing the activity of transcription factors, affecting the synthesis of proteins involved in various cellular functions.
In summary, thrombin-activated receptor activity is a multifaceted process that involves the proteolytic cleavage of PARs, leading to the activation of G proteins, calcium signaling, MAP kinase signaling, and cytoskeletal rearrangement. These events ultimately result in a diverse range of physiological responses, including platelet aggregation, smooth muscle contraction, inflammation, and tissue repair.'
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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) |
Compound | Definition | Classes | Roles |
---|---|---|---|
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 | |
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 | ||
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 |