Protease-activated receptor

From Wikipedia, the free encyclopedia
Jump to: navigation, search
coagulation factor II (thrombin) receptor
Identifiers
Symbol F2R
Alt. symbols PAR1
Entrez 2149
HUGO 3537
OMIM 187930
RefSeq NM_001992
UniProt P25116
Other data
Locus Chr. 5 q13
coagulation factor II (thrombin) receptor-like 1
Identifiers
Symbol F2RL1
Alt. symbols PAR2, GPR11
Entrez 2150
HUGO 3538
OMIM 600933
RefSeq NM_005242
UniProt P55085
Other data
Locus Chr. 5 q13
coagulation factor II (thrombin) receptor-like 2
Identifiers
Symbol F2RL2
Alt. symbols PAR3
Entrez 2151
HUGO 3539
OMIM 601919
RefSeq NM_004101
UniProt O00254
Other data
Locus Chr. 5 q13
coagulation factor II (thrombin) receptor-like 3
Identifiers
Symbol F2RL3
Alt. symbols PAR4
Entrez 9002
HUGO 3540
OMIM 602779
RefSeq NM_003950
UniProt Q96RI0
Other data
Locus Chr. 19 p12

Protease-activated receptors 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, but also on endothelial cells, myocytes and neurons.[1]

Classification[edit]

There are 4 known protease-activated receptors or PARs, numbered from one to four. These receptors are members of the seven transmembrane G-protein-coupled receptor superfamily, and are expressed throughout the body.

Activation[edit]

Protease activated receptors are integral membrane proteins that are coupled to G-proteins and are activated by specific cleavage of the amino terminal sequence that exposes a new N-terminal sequence functions as a tethered ligand, which binds intramolecularly to activate the receptor.[2] Four types of PAR receptors have been identified by molecular cloning, and classified according to the main enzyme that is able to activate it. It has been determined that a large group of proteases that cleave and activate PARs receptors including proteases from: a) the coagulation cascade, b) inflammatory cells, and c) the digestive tract. The wide distribution of PARs in a variety of cells supports the idea that they are involved in many process related with the gastrointestinal physiology.[3] Although the proteolysis is the main mechanism for PAR activation, it is well known that a synthetic peptide (SLIGKV) that mimics the new N-terminal sequence produced after the cleavage, activates PAR-2 receptors without its proteolytic processing. In this sense, here we report that TFF3 isolated from human breast milk activates PAR-2 receptors of intestinal epithelial cells HT-29. These findings suggest that TFF3 activates intestinal epithelial cells through G-protein-coupled PAR-2, and could actively participate in the immune system of breastfed babies inducing the production of peptides related to innate defense, such as defensins and cytokines.[4]

PARs are activated by the action of serine proteases such as thrombin (acts on PARs 1, 3 and 4) and trypsin (PAR 2).[5] These enzymes cleave the N-terminus of the receptor, which in turn acts as a tethered ligand. In the cleaved state, part of the receptor itself acts as the agonist, causing a physiological response.

Most of the PAR family act through the actions of G-proteins i (cAMP inhibitory), 12/13 (Rho and Ras activation) and q (calcium signalling) to cause cellular actions.

Function[edit]

The cellular effects of thrombin are mediated by protease-activated receptors (PARs). Thrombin signalling in platelets contributes to hemostasis and thrombosis. Endothelial PARs participate in the regulation of vascular tone and permeability while in vascular smooth muscle they mediate contraction, proliferation, and hypertrophy. PARs contribute to the pro-inflammatory response observed in atherosclerosis and restenosis. Recent research has also implicated these novel receptors in muscle growth and bone cell differentiation and proliferation.[6]

In T cells, activation of PAR1, PAR2 and PAR3 induce tyrosine phosphorylation of VAV1. Activation of PARs also led to an increase in tyrosine phosphorylation of ZAP-70 and SLP-76, two key proteins in T cell receptor (TCR) signalling.[7]

References[edit]

  1. ^ Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R (2001). "Proteinase-activated receptors" (abstract). Pharmacol Rev. 53 (2): 245–82. PMID 11356985. 
  2. ^ Barrera, G. J., & Tortolero, G. S. (2016). Trefoil factor 3 (TFF3) from human breast milk activates PAR-2 receptors, of the intestinal epithelial cells HT-29, regulating cytokines and defensins. Bratislavské lekárske listy, 117(6), 332.
  3. ^ Barrera, G. J., & Tortolero, G. S. (2016). Trefoil factor 3 (TFF3) from human breast milk activates PAR-2 receptors, of the intestinal epithelial cells HT-29, regulating cytokines and defensins. Bratislavské lekárske listy, 117(6), 332.
  4. ^ Barrera, G. J., & Tortolero, G. S. (2016). Trefoil factor 3 (TFF3) from human breast milk activates PAR-2 receptors, of the intestinal epithelial cells HT-29, regulating cytokines and defensins. Bratislavské lekárske listy, 117(6), 332.
  5. ^ Coughlin SR, Camerer E (January 2003). "PARticipation in inflammation". J. Clin. Invest. 111 (1): 25–7. doi:10.1172/JCI17564. PMC 151847Freely accessible. PMID 12511583. 
  6. ^ Martorell L, Martínez-González J, Rodríguez C, Gentile M, Calvayrac O, Badimon L (February 2008). "Thrombin and protease-activated receptors (PARs) in atherothrombosis". Thromb. Haemost. 99 (2): 305–15. doi:10.1160/TH07-08-0481. PMID 18278179. 
  7. ^ Bar-Shavit R, Maoz M, Yongjun Y, Groysman M, Dekel I, Katzav S (January 2002). "Signalling pathways induced by protease-activated receptors and integrins in T cells". Immunology. 105 (1): 35–46. doi:10.1046/j.0019-2805.2001.01351.x. PMC 1782632Freely accessible. PMID 11849313. 

External links[edit]