Thrombin receptor
There are three known thrombin receptors (ThrR[1]), termed PAR1, PAR3 and PAR4 (PAR for protease-activated receptor).[2]
G-protein-coupled receptors that are responsible for the coagulation effects and responses of thrombin on cells are known as protease-activated receptors, or PARs. These receptors are members of the 7-transmembrane g protein-coupled family of receptors, however, their method of activation is unique. Unlike most G-protein-coupled receptors, PARs are irreversibly activated by proteolytic mechanism and therefore, are strictly regulated.
Thrombin is an allosteric serine protease that is an essential effector of coagulation that is produced at sites of vascular injury and plays a critical role in cellular response to blood-related diseases.[3] It binds to and cleaves the extracellular N-terminal domain of the receptor. A tethered ligand corresponding to the new N-terminus, SFLLRN, is then unmasked, binding to the second extracellular loop of the receptor and activating it.
Tissue distribution
PAR1, PAR3, and PAR4 are activated by thrombin.[4] There are species-specific differences in thrombin receptor expression in platelets and other cell types,[5] in which differences in thrombin concentrations may considerably affect platelet activation of distinct PARs.[6] As seen in human platelets, PAR1 and PAR4 are the functional thrombin receptors, whereas PAR3 and PAR4 are functional thrombin receptors in mouse platelets
Thrombin receptors are also differentially expressed in cell types, e.g. PAR1 is expressed in fibroblasts, smooth muscle cells, sensory neurons and glial cells, whereas the other two are less clearly defined.
There are various roles depending on location of activation. Fibroblasts and smooth muscle cells induces growth factor and matrix production, migration and proliferation. Sensory neurons induces proliferation and release of neuroactive agents.
Regulation of signaling
Desensitization and internalization
Initial desensitization due to rapid phosphorylation of activated receptors by kinases, which increases affinity for arrestin. Arrestin prevents protein-receptor interaction and the receptor becomes dephosphorylated and inhibited from signaling.[7] This is a sufficient and rapid form of termination of PAR signaling. Irreversibly activated PAR1 is internalized and terminated from further signaling by clathrin-mediated endocytosis and lysosome degradation, preventing replenishment at the cell surface.[7]
References
- ^ Darrow AL, Fung-Leung WP, Ye RD, Santulli RJ, Cheung WM, Derian CK, et al. (December 1996). "Biological consequences of thrombin receptor deficiency in mice". Thrombosis and Haemostasis. 76 (6): 860–866. doi:10.1055/s-0038-1650676. PMID 8972001. S2CID 13524388.
- ^ Cirino G, Severino B (July 2010). "Thrombin receptors and their antagonists: an update on the patent literature". Expert Opinion on Therapeutic Patents. 20 (7): 875–884. doi:10.1517/13543776.2010.487864. PMID 20450349. S2CID 6409635.
- ^ Heuberger DM, Schuepbach RA (December 2019). "Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases". Thrombosis Journal. 17 (1): 4. doi:10.1186/s12959-019-0194-8. PMC 6440139. PMID 30976204.
- ^ Rand ML, Israels S (2018). "Molecular Basis of Platelet Function". Hematology. Elsevier. pp. 1870–1884.e2. doi:10.1016/b978-0-323-35762-3.00125-6. ISBN 9780323357623.
- ^ Clemetson KJ, Clemetson JM (2013). "Platelet Receptors". Platelets. Elsevier. pp. 169–194. doi:10.1016/b978-0-12-387837-3.00009-2. ISBN 9780123878373.
- ^ Kahn ML, Zheng YW, Huang W, Bigornia V, Zeng D, Moff S, et al. (August 1998). "A dual thrombin receptor system for platelet activation". Nature. 394 (6694): 690–694. Bibcode:1998Natur.394..690K. doi:10.1038/29325. PMID 9716134. S2CID 4408582.
- ^ a b Trejo JA (2009). "Regulation of Thrombin Receptor Signaling". In Maragoudakis ME, Tsopanoglou NE (eds.). Thrombin. New York, NY: Springer New York. pp. 47–61. doi:10.1007/978-0-387-09637-7_3. ISBN 9780387096360. OCLC 1012579608.
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