Evidence for the presence of a protease-activated receptor distinct from the thrombin receptor in human keratinocytes.

Abstract

Thrombin receptor activation was explored in human epidermal keratinocytes and human dermal fibroblasts, cells that are actively involved in skin tissue repair. The effects of thrombin, trypsin, and the receptor agonist peptides SFLLRN and TFRIFD were assessed in inositolphospholipid hydrolysis and calcium mobilization studies. Thrombin and SFLLRN stimulated fibroblasts in both assays to a similar extent, whereas TFRIFD was less potent. Trypsin demonstrated weak efficacy in these assays in comparison with thrombin. Results in fibroblasts were consistent with human platelet thrombin receptor activation. Keratinocytes, however, exhibited a distinct profile, with trypsin being a far better activator of inositolphospholipid hydrolysis and calcium mobilization than thrombin. Furthermore, SFLLRN was more efficacious than thrombin, whereas no response was observed with TFRIFD. Since our data indicated that keratinocytes possess a trypsin-sensitive receptor, we addressed the possibility that these cells express the human homologue of the newly described murine protease-activated receptor, PAR-2

Thrombin, but not bradykinin, stimulates proliferation in isolated human osteoblasts, via a mechanism not dependent on endogenous prostaglandin formation

“…Thrombin, a serin protease that plays an important role in the blood coagulation cascade through its cleavage of fibrinogen to fibrin, has been reported to have hormone-like receptor-mediated effects in various types of cells, including bone cells (Fenton 1988). On activation, these receptors signal via intracellular calcium and prostaglandin formation and the thrombin receptor responds to the activating peptide in a manner previously described (Santulli et al 1995).…”

Presence of functionally active protease‐activated receptors 1 and 2 in myenteric glia

“…Recently, PAR-1 expression has been reported in neurons of the ENS (Corvera et al 1999). PAR-2 is also widely expressed; it has been demonstrated in vascular tissue, the digestive system and epidermis (Al-Ani et al 1995 21 ; Santulli et al 1995;Derian and Eckardt 1997;D'Andrea et al 1998;Corvera et al 1999). Within the gastrointestinal tract, PAR-2 has been reported in enterocytes, smooth muscle cells and myenteric neurons.…”

Trypsin Stimulates Integrin α5β1-dependent Adhesion to Fibronectin and Proliferation of Human Gastric Carcinoma Cells through Activation of Proteinase-activated Receptor-2

“…Effects of PAR-1 and PAR-2 Activation on Adhesion of MKN-1 Cells-It has been reported that trypsin activates PAR-2 efficiently, stimulating signal transduction through G proteins (23,25). Therefore, the activation of PARs seemed to be a possible mechanism for the stimulatory effect of trypsin on adhesion of MKN-1 cells to fibronectin.…”

“…PAR-1 (thrombin receptor) and PAR-3, which are expressed mainly in platelets, endothelium, and leukocytes, are effectively activated by thrombin (23,24). In contrast, PAR-2, which is expressed in a wide variety of epithelial tissues, endothelial cells, T cells, smooth muscle cells and tumor cell lines, is activated by trypsin but not by thrombin (22,(25)(26)(27). Recently found PAR-4 is highly expressed in the lung, thyroid, testis, and small intestine, and activated by both thrombin and trypsin (28).…”

“…Recently found PAR-4 is highly expressed in the lung, thyroid, testis, and small intestine, and activated by both thrombin and trypsin (28). In common to G protein-coupled receptors (GPCRs), activated PARs induce G protein-mediated signal transduction, stimulating generation of inositol 1,4,5-triphosphate, intracellular calcium mobilization, arachidonic acid release, and prostaglandin secretion (22,25,27). Thus PARs are thought to be involved in various pathophysiological processes, including development, cell growth and inflammation (22).…”