Protease-activated receptor signaling

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. 

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). 

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

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. 

Di Cera E. Thrombin. Mol Aspects Med. 2008 29 203-254. Esmon CT. The protein C pathway. Chest 2003 124 26S-32S. ConghUn SR. Thrombin signalling and protease-activated receptors. Natnre 2000 407 258-264. 

Sabri A, Muske G, Zhang H, et al. Signaling properties and functions of two distinct cardiomyocyte protease-activated receptors. Circ Res 2000 86 1054-1061. 

Vergnolle, N., Wallace, J.L., Bunnett, N.W. and Hollenberg, M.D. (2001) Protease-activated receptors in inflammation, neuronal signaling and pain. Trends Pharmacol. Sci. 22 146-152. 

Carmo, A. A., Costa, B. R., Vago, J. P., de Ohveira, L. C., Tavares, L. P., Nogueira, C. R., et al. (2014). Plasmin induces in vivo monocyte recruitment through protease-activated receptor-1-, MEK/ERK-, and CCR2-mediated signaling. Jouma/ of Immunology, 193(7), 3654-3663. 

Fig. 1. Proposed mechanism of action of rituximab associated with the apoptosis pathway. Binding of rituximab with the CD20 antigen up-regulates the production of interleukin-10 (IL-10). The IL-10 autocrine loop down-regulates the expression of the bcl-2 protein, which inhibits the intrinsic pathway (or mitochondrial mediated pathway) of apoptosis. The mitochondrial pathway is induced by intracellular stress signals. The translocation of the bcl-2 protein into the mitochondria leads to the activation of caspase 9 via release of cytochrome c and apoptotic protease-activating factor 1. The other pathway, the extrinsic pathway (or death receptor mediated pathway) activates caspase 8. Subsequently, caspase 8 or 9 activates caspase 3, leading to programmed cell death (apoptosis).

FIGURE 12-50 Initial events of apoptosis. Receptors in the plasma membrane (Fas, TNF-R1) receive signals from outside the cell (the Fas ligand or tumor necrosis factor (TNF), respectively). Activated receptors foster interaction between the "death domain" (an 80 amino acid sequence) in Fas or TNF-R1 and a similar death domain in the cytosolic proteins FADD or TRADD. FADD activates a cytosolic protease, caspase 8, that proteolytically activates other cellular proteases. TRADD also activates proteases. The resulting proteolysis is a primary factor in cell death. 

Dery, O., Corvera, C.U., Steinhoff, M. and Bunnett, N.W. (1998) Proteinase-activated receptors novel mechanisms of signaling by serine proteases. Am. J. Physiol. 274 C1429-C1452. 

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