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Journal Article

Proteinase-activated receptors

01 Jan 2001-Pharmacological Research-Vol. 53, pp 245-282
TL;DR: The role of thrombin in such processes as wound healing and the evidence implicating PAR-1 in vascular disorders and cancer are described and advances in the understanding ofPAR-1-mediated intracellular signaling and receptor desensitization are identified.
About: This article is published in Pharmacological Research.The article was published on 2001-01-01 and is currently open access. It has received 922 citations till now. The article focuses on the topics: Protease-activated receptor.
Citations
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Journal ArticleDOI
TL;DR: Only mast cells in close proximity to nerves were significantly correlated with severity and frequency of abdominal pain/discomfort, and mediator release in proximity to mucosal innervation may contribute to abdominal pain perception in IBS patients.

1,310 citations

Journal ArticleDOI
TL;DR: Major future challenges will be to understand the role of proteases and PARs in physiological control mechanisms and human diseases and to develop selective agonists and antagonists that can be used to probe function and treat disease.
Abstract: Proteases acting at the surface of cells generate and destroy receptor agonists and activate and inactivate receptors, thereby making a vitally important contribution to signal transduction. Certain serine proteases that derive from the circulation (e.g., coagulation factors), inflammatory cells (e.g., mast cell and neutrophil proteases), and from multiple other sources (e.g., epithelial cells, neurons, bacteria, fungi) can cleave protease-activated receptors (PARs), a family of four G protein-coupled receptors. Cleavage within the extracellular amino terminus exposes a tethered ligand domain, which binds to and activates the receptors to initiate multiple signaling cascades. Despite this irreversible mechanism of activation, signaling by PARs is efficiently terminated by receptor desensitization (receptor phosphorylation and uncoupling from G proteins) and downregulation (receptor degradation by cell-surface and lysosomal proteases). Protease signaling in tissues depends on the generation and release of proteases, availability of cofactors, presence of protease inhibitors, and activation and inactivation of PARs. Many proteases that activate PARs are produced during tissue damage, and PARs make important contributions to tissue responses to injury, including hemostasis, repair, cell survival, inflammation, and pain. Drugs that mimic or interfere with these processes are attractive therapies: selective agonists of PARs may facilitate healing, repair, and protection, whereas protease inhibitors and PAR antagonists can impede exacerbated inflammation and pain. Major future challenges will be to understand the role of proteases and PARs in physiological control mechanisms and human diseases and to develop selective agonists and antagonists that can be used to probe function and treat disease.

1,036 citations


Cites background from "Proteinase-activated receptors"

  • ...The mechanisms of PAR1 and PAR2 signaling have been extensively investigated and reviewed (89, 182)....

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  • ...The characteristics of PAR APs and their utility as templates for design of antagonists have been recently reviewed in detail (182) and are only summarized here....

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Journal ArticleDOI
TL;DR: Downregulation of MMPs using genetic manipulations of endogenous TIMPs, or synthetic pharmacological inhibitors such as BB-94 (Batimastat and doxycycline, and Ro-28-2653, a more specific inhibitor of gelatinases and membrane type 1-MMP, could be beneficial in reducing the MMP-mediated vascular dysfunction and the progressive vessel wall damage associated with vascular disease.

686 citations

Journal ArticleDOI
TL;DR: Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin.
Abstract: This review focuses on the role of the peripheral nervous system in cutaneous biology and disease. During the last few years, a modern concept of an interactive network between cutaneous nerves, the neuroendocrine axis, and the immune system has been established. We learned that neurocutaneous interactions influence a variety of physiological and pathophysiological functions, including cell growth, immunity, inflammation, pruritus, and wound healing. This interaction is mediated by primary afferent as well as autonomic nerves, which release neuromediators and activate specific receptors on many target cells in the skin. A dense network of sensory nerves releases neuropeptides, thereby modulating inflammation, cell growth, and the immune responses in the skin. Neurotrophic factors, in addition to regulating nerve growth, participate in many properties of skin function. The skin expresses a variety of neurohormone receptors coupled to heterotrimeric G proteins that are tightly involved in skin homeostasis and inflammation. This neurohormone-receptor interaction is modulated by endopeptidases, which are able to terminate neuropeptide-induced inflammatory or immune responses. Neuronal proteinase-activated receptors or transient receptor potential ion channels are recently described receptors that may have been important in regulating neurogenic inflammation, pain, and pruritus. Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin. A deeper understanding of cutaneous neuroimmunoendocrinology may help to develop new strategies for the treatment of several skin diseases.

534 citations

Journal ArticleDOI
TL;DR: Osteoarthritis is characterized by degradation and loss of articular cartilage, subchondral bone remodeling, and, at the clinical stage of the disease, inflammation of the synovial membrane.
Abstract: The preservation of articular cartilage depends on keeping the cartilage architecture intact. Cartilage strength and function depend on both the properties of the tissue and on their structural parameters. The main structural macromolecules are collagen and proteoglycans (aggrecan). During life, cartilage matrix turnover is mediated by a multitude of complex autocrine and paracrine anabolic and catabolic factors. These act on the chondrocytes and can lead to repair, remodeling or catabolic processes like those that occur in osteoarthritis. Osteoarthritis is characterized by degradation and loss of articular cartilage, subchondral bone remodeling, and, at the clinical stage of the disease, inflammation of the synovial membrane. The alterations in osteoarthritic cartilage are numerous and involve morphologic and metabolic changes in chondrocytes, as well as biochemical and structural alterations in the extracellular matrix macromolecules.

511 citations

References
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Journal ArticleDOI
31 Mar 1988-Nature
TL;DR: Cloning and sequencing of preproendothelin complementary DNA shows that mature endothelin is generated through an unusual proteolytic processing, and regional homologies to a group of neurotoxins suggest that endothelins is an endogenous modulator of voltage-dependent ion channels.
Abstract: An endothelium-derived 21-residue vasoconstrictor peptide, endothelin, has been isolated, and shown to be one of the most potent vasoconstrictors known. Cloning and sequencing of preproendothelin complementary DNA shows that mature endothelin is generated through an unusual proteolytic processing, and regional homologies to a group of neurotoxins suggest that endothelin is an endogenous modulator of voltage-dependent ion channels. Expression of the endothelin gene is regulated by several vasoactive agents, indicating the existence of a novel cardiovascular control system.

10,651 citations


"Proteinase-activated receptors" refers background in this paper

  • ...…the production and release of promitogenic factors, such as PDGF and ET-1 through induction of PDGF and ET-1 prepro mRNA (Daniel et al., 1986; Yanagisawa et al., 1988; Garcia et al., 1993; Golden et al., 1998) and also regulates the subsequent release of these factors, in particular ET-1…...

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Journal ArticleDOI
22 Mar 1991-Cell
TL;DR: A novel signaling mechanism in which thrombin cleaves its receptor's amino-terminal extension to create a new receptor amino terminus that functions as a tethered ligand and activates the receptor is revealed.

2,992 citations


"Proteinase-activated receptors" refers background in this paper

  • ...Mutation of the N terminus identified the presence of a hirudin-like domain within region 51–63 that was essential for high affinity binding and the potent effects of thrombin (Vu et al., 1991b)....

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  • ...Furthermore, responses to thrombin were found to be blocked by the thrombin antagonists hirudin and hirugen, a hirudin-derived peptide (Vu et al., 1991a) indicative of the thrombin-specific nature of the cloned receptor....

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  • ...In 1991, Coughlin and colleagues (Vu et al., 1991a) used a dilution cloning approach in an attempt to isolate the cDNA encoding the thrombin receptor....

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  • ...Mutation of this residue, Arg41 to Ala, rendered the receptor insensitive to stimulation when expressed in oocytes (Vu et al., 1991a), whereas a peptide mimicking the new amino terminus created by cleavage at Arg41, SFLLRNPNDKYEPF (TRAP-14), was able to activate both wild-type and mutant receptors....

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  • ...A mutant receptor with the LDPR/S site replaced by an enterokinase site was fully responsive to enterokinase, suggesting no require- ment for an additional mechanism of activation other than that initially proposed (Vu et al., 1991b)....

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Journal ArticleDOI
14 Sep 2000-Nature
TL;DR: Roles for PARs are beginning to emerge in haemostasis and thrombosis, inflammation, and perhaps even blood vessel development.
Abstract: How does the coagulation protease thrombin regulate cellular behaviour? The protease-activated receptors (PARs) provide one answer. In concert with the coagulation cascade, these receptors provide an elegant mechanism linking mechanical information in the form of tissue injury or vascular leakage to cellular responses. Roles for PARs are beginning to emerge in haemostasis and thrombosis, inflammation, and perhaps even blood vessel development.

2,354 citations


"Proteinase-activated receptors" refers background in this paper

  • ...Such is the rapidly expansive nature of the field; the reader is directed to a number of excellent recent shorter reviews that will complement this current work (Grand et al., 1996; Hollenberg, 1996; Dery et al., 1998; Cocks and Moffatt, 2000; Coughlin, 2000)....

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Journal ArticleDOI
05 Feb 1998-Nature
TL;DR: In this paper, platelets express CD40L within seconds of activation in vitro and in the process of thrombus formation in vivo, indicating that platelets are not only involved in haemostasis but that they also directly initiate an inflammatory response of the vessel wall.
Abstract: CD40 ligand (CD40L, CD154), a transmembrane protein structurally related to the cytokine TNF-alpha, was originally identified on stimulated CD4+ T cells, and later on stimulated mast cells and basophils. Interaction of CD40L on T cells with CD40 on B cells is of paramount importance for the development and function of the humoral immune system. CD40 is not only constitutively present on B cells, but it is also found on monocytes, macrophages and endothelial cells, suggesting that CD40L has a broader function in vivo. We now report that platelets express CD40L within seconds of activation in vitro and in the process of thrombus formation in vivo. Like TNF-alpha and interleukin-1, CD40L on platelets induces endothelial cells to secrete chemokines and to express adhesion molecules, thereby generating signals for the recruitment and extravasation of leukocytes at the site of injury. Our results indicate that platelets are not only involved in haemostasis but that they also directly initiate an inflammatory response of the vessel wall.

2,045 citations


"Proteinase-activated receptors" refers background in this paper

  • ...In addition, thrombin also mediates the translocation of P-selectin and CD40 ligand to the plasma membrane, which facilitate the binding of platelets to endothelial cells (Stenberg et al., 1985; Henn et al., 1998)....

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  • ...Thrombin released from platelets stimulates the release of von Willebrand factor, cell surface redistribution of P-selectin, and increased expression of tissue factor and adhesion molecules, ICAM-1, VCAM-1, and E-selectin (Hattori et al., 1989; Bartha et al., 1993; Henn et al., 1998)....

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Journal ArticleDOI

1,803 citations


"Proteinase-activated receptors" refers background in this paper

  • ...Thrombin was originally identified as a trypsin-like serine protease, produced from prothrombin by the action of factor Xa, which mediated the formation of fibrin, the fibrous matrix of blood clots, from fibrinogen (Davie et al., 1991; Stubbs and Bode, 1993)....

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