Thrombin receptor

Last updated

There are three known thrombin receptors (ThrR [1] ), termed PAR1, PAR3 and PAR4 (PAR for protease-activated receptor). [2]

Contents

Activation of PARs Activation of PAR.png
Activation of PARs

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 [7]

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. 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.

Related Research Articles

G protein-coupled receptor Class of cell surface receptors coupled to G-Protein associated intracelular signaling

G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times. Ligands can bind either to extracellular N-terminus and loops or to the binding site within transmembrane helices. They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed.

Platelet Component of blood aiding in coagulation

Platelets, also called thrombocytes, are a component of blood whose function is to react to bleeding from blood vessel injury by clumping, thereby initiating a blood clot. Platelets have no cell nucleus; they are fragments of cytoplasm that are derived from the megakaryocytes of the bone marrow or lung, which then enter the circulation. Circulating inactivated platelets are biconvex discoid (lens-shaped) structures, 2–3 µm in greatest diameter. Activated platelets have cell membrane projections covering their surface. Platelets are found only in mammals, whereas in other vertebrates, thrombocytes circulate as intact mononuclear cells.

Coagulation Process by which blood changes from a liquid to a gel, forming a blood clot

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

Thrombin Enzyme in humans

Thrombin is a serine protease, an enzyme that, in humans, is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the clotting process. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.

Protease-activated receptors (PAR) are a subfamily of related G protein-coupled receptors that are activated by cleavage of part of their extracellular domain. They are highly expressed in platelets, and also on endothelial cells, myocytes and neurons.

Tissue factor

Tissue factor, also called platelet tissue factor, factor III, or CD142, is a protein encoded by the F3 gene, present in subendothelial tissue and leukocytes. Its role in the clotting process is the initiation of thrombin formation from the zymogen prothrombin. Thromboplastin defines the cascade that leads to the activation of factor X—the tissue factor pathway. In doing so, it has replaced the previously named extrinsic pathway in order to eliminate ambiguity.

The actions of vasopressin are mediated by stimulation of tissue-specific G protein-coupled receptors (GPCRs) called vasopressin receptors that are classified into the V1 (V1A), V2, and V3 (V1B) receptor subtypes. These three subtypes differ in localization, function and signal transduction mechanisms.

Arrestin

Arrestins are a small family of proteins important for regulating signal transduction at G protein-coupled receptors. Arrestins were first discovered as a part of a conserved two-step mechanism for regulating the activity of G protein-coupled receptors (GPCRs) in the visual rhodopsin system by Hermann Kühn, Scott Hall, and Ursula Wilden and in the β-adrenergic system by Martin J. Lohse and co-workers.

G protein-coupled receptor kinase

G protein-coupled receptor kinases are a family of protein kinases within the AGC group of kinases. Like all AGC kinases, GRKs use ATP to add phosphate to Serine and Threonine residues in specific locations of target proteins. In particular, GRKs phosphorylate intracellular domains of G protein-coupled receptors (GPCRs). GRKs function in tandem with arrestin proteins to regulate the sensitivity of GPCRs for stimulating downstream heterotrimeric G protein and G protein-independent signaling pathways.

Kininogens are precursor proteins for kinins, biologically active polypeptides involved in blood coagulation, vasodilation, smooth muscle contraction, inflammatory regulation, and the regulation of the cardiovascular and renal systems.

Thromboxane receptor

The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the TBXA2R gene, The thromboxane receptor is one among the five classes of prostanoid receptors and was the first eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.

LRP1

Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis. In humans, the LRP1 protein is encoded by the LRP1 gene. LRP1 is also a key signalling protein and, thus, involved in various biological processes, such as lipoprotein metabolism and cell motility, and diseases, such as neurodegenerative diseases, atherosclerosis, and cancer.

F2RL2

Protease activated receptor 3 (PAR-3) also known as coagulation factor II receptor-like 2 (F2RL2) and thrombin receptor-like 2, is a protein that in humans is encoded by the F2RL2 gene.

Protease-activated receptor 2

Protease activated receptor 2 (PAR2) also known as coagulation factor II (thrombin) receptor-like 1 (F2RL1) or G-protein coupled receptor 11 (GPR11) is a protein that in humans is encoded by the F2RL1 gene. PAR2 modulates inflammatory responses, obesity, metabolism, cancers and acts as a sensor for proteolytic enzymes generated during infection. In humans, we can find PAR2 in the stratum granulosum layer of epidermal keratinocytes. Functional PAR2 is also expressed by several immune cells such as eosinophils, neutrophils, monocytes, macrophages, dendritic cells, mast cells and T cells.

Coagulation factor II receptor

Proteinase-activated receptor 1 (PAR1) also known as Protease-activated receptor 1 or coagulation factor II (thrombin) receptor is a protein that in humans is encoded by the F2R gene. PAR1 is a G protein-coupled receptor and one of four protease-activated receptors involved in the regulation of thrombotic response. Highly expressed in platelets and endothelial cells, PAR1 plays a key role in mediating the interplay between coagulation and inflammation, which is important in the pathogenesis of inflammatory and fibrotic lung diseases. It is also involved both in disruption and maintenance of endothelial barrier integrity, through interaction with either thrombin or activated protein C, respectively.

Arrestin beta 2

Beta-arrestin-2, also known as arrestin beta-2, is an intracellular protein that in humans is encoded by the ARRB2 gene.

F2RL3

Protease-activated receptor 4 (PAR-4), also known as coagulation factor II (thrombin) receptor-like 3, is a protein that in humans is encoded by the F2RL3 gene.

GRK6

This gene encodes a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinase family, and is most highly similar to GRK4 and GRK5. The protein phosphorylates the activated forms of G protein-coupled receptors to regulate their signaling.

GRK5

G protein-coupled receptor kinase 5 is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases, and is most highly similar to GRK4 and GRK6. The protein phosphorylates the activated forms of G protein-coupled receptors to regulate their signaling.

Collagen receptors are membrane proteins that bind the extracellular matrix protein collagen, the most abundant protein in mammals. They control mainly cell proliferation, migration and adhesion, coagulation cascade activation and they affect ECM structure by regulation of MMP.

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ Clemetson KJ, Clemetson JM (2013). "Platelet Receptors". Platelets. Elsevier. pp. 169–194. doi:10.1016/b978-0-12-387837-3.00009-2. ISBN   9780123878373.
  6. ↑ 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.
  7. ↑ 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   978-0-387-09636-0.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.