Protease-activated receptors

Protease-activated receptors, PAR-1, PAR-2, PAR-3, PAR-4 Thrombin receptors Thrombin-related receptors, Trypsin receptor... 

Barry GD, Le GT, Fairlie DP (2006) Agonists and antagonists of protease-activated receptors (PARs). Curr MedChem 13 243-265... 

Leger AJ, Covic L, Kuliopulos A (2006) Protease-activated receptors in cardiovascular disease. Circulation 114 1070-1077... 

Ossovskaya VS, Bunnett NW (2003) Protease-activated receptors contribution to physiology and disease. Physiol Rev 84 579-621... 

Most GPCRs interact with and activate more than one G-protein subfamily, e.g., with Gs plus Gq/n (histamine H2, parathyroid hormone and calcitonin recqrtors), Gs plus G (luteinising hormone receptor, 32-adrenoceptor) or Gq/11 plus G12/13 (thromboxane A2, angiotensin ATb endothelin ETA receptors). Some receptors show even broader G-protein coupling, e.g., to Gi, Gq/n plus Gi n ( protease-activated receptors, lysophosphatidate and sphingosine-1-phosphate receptors) or even to all four G-protein subfamilies (thyrotropin receptor). This multiple coupling results in multiple signaling via different pathways and in a concerted reaction of the cell to the stimulus. 

TRPVl also plays a central role in intercellular pro-inflammatory feedback loops. An important example is mast cells and sensory nerves. Mast cells release tryptase that, in turn, activates the protease-activated receptor PAR-2 activation of PAR-2 then opens TRPVl via PKC [50]. In keeping with this, PAR-2 agonists reduce the heat activation threshold of TRPVl from 42 °C to below body temperature [51]. Excited nerve endings release SP that, as a positive feedback, binds to neurokinin NKl receptors on mast cells. Mast cells also express TRPVl [52]. Consequently, endovanilloids can act in concert to stimulate mast cells and activate capsaicin-sensitive nerve endings. Of relevance is the finding that PAR-2 is up-regulated in the bladder during experimental cystitis [53]. 

The protease activated receptors PAR-1 to PARA, of which PAR-1 is the thrombin receptor and PAR-2 conceivably a Factor-VIIa receptor, are particularly interesting cases. The ligands for these receptors are part of the N-terminal extension of the receptor. The enzyme (for example, thrombin) will bind and cleave off most of this extracellular segment and thereby reveal a new,... 

The protease-activated receptors (PARs), a subclass of GPCRs that function in the coagulation cascade, suggest that a comprehensive survey of the GPCR portion of the proteome provides information about the structure and function of this receptor class. The PAR factor II (thrombin) receptor-like 2 (F2RL2) is inactive in the cascade until proteolytic cleavage of its extracellular amino terminus. A Phe240Ser variant that is located in the second intracellular loop, found at a frequency of approx. 8%, disrupts receptor activation by proteolysis. 

Compton, S. J., Cairns, J. A., Palmer, K. J., Al Ani, B., and HoUenberg, M. D. (2001) A polymorphic protease activated receptor 2 (PAR2) displaying reduced sensitivity to trypsin and differential responses to PAR agonists. FASEB J. 15, A931. 

Coughlin, S. R. (2001) Protease-activated receptors in vascular biology. Thromb. Haemost. 86, 298-307. 

Thrombin, a serine protease, cleaves fibrinogen into fibrin to create a fibrous plug and also amplifies its own production through the activation of factor XI and cofactors V and Vlll. Thrombin also plays a crucial role in the activation of platelets through the cleavage of the protease-activated receptors on the platelet surface. Antagonists of G-protein-coupled protease-activated receptor PARi have been synthesised to study the role of thrombin PARi receptor in thrombosis and vascular injury. Thrombosis is the most common cause of death in the industrialised world and, whether through venous thromboembolism, myocardial infarction or stroke, ultimately involves the inappropriate activity of... 

Activation of receptors can also be mediated by proteolytic cleavage of the extracellular domain of the receptor by proteases like thrombin. For these protease activated receptors, a proteolytically produced peptide functions as the activating ligand. 

McLaughlin, J. N., Shen, L., Holinstat, M., Brooks, J. D., Dibenedetto, E., and Hamm, H. E. (2005). Functional selectivity of G protein signaling by agonist peptides and thrombin for the protease-activated receptor-1. / Biol. Chem. 280, 25048-25059. 

Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000 407 258-264. 

Thrombin and collagen are the strongest platelet agonists. Thrombin signaling is mediated by a family of G protein-coupled receptors, termed protease-activated receptors (PARs). Four PARs have been identified (PAR-1 through PAR-4) PAR-1, PAR-3, and PAR-4 are thrombin receptors (18). PAR-2 can be activated by trypsin and tryptase, but not by thrombin (19). 

Ishihara H, Connolly AJ, Zeng D, et al, Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 1997 386 502-506. 

Adenosine receptor agonists Protease-activated receptor agonists GAGs... 

Junge CE, Sugawara T, Mannaioni G, Alagarsamy S, Conn PJ, Brat DJ, Chan PH, Traynelis SF (2003) The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia. Proc Natl Acad Sci USA 100 13019-13024... 

Trypsin is typically considered an enzyme found in the pancreas and small intestine. However, trypsin, thrombin, and plasmin are also widely expressed in endothelium, including epithelial immune cells as well as neurons. Upregulated expression and release occurs during both acute and chronic inflammation [60], Autocrine release of trypsin and thrombin causes activation of protease-activated receptors (PARs) reaction leading to cellular proliferation and inflammation [4], This response includes release of proteins by all cells during chronic inflammation. Bik prevents PAR activation on cell surfaces. 

Cocks T, Moffatt J. Protease-activated receptors Sentries for inflammation. Trends Pharmacol Sci 2000 21 103-108. 

Cottrell G. Protease activated receptors The role of cell surface proteolysis in signaling. Essays Biochem 2002 38 169-183. 

Miike S, McWilliam A, Kita H. Trypsin induces activation and inflammatory mediator release from human eosinophils through protease-activated receptor-2. J Immunol 2001 167 6615-6622. 

Rohatgi T, Sedehizade F, Reymann KG, Reiser G. Protease-activated receptors in neuronal development, neurodegeneration, and neuroprotection Thrombin as signaling molecule in the brain. Neuroscientist 2004 10 501-512. 

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