Protease-activated receptors: the role of cell-surface proteolysis in signalling

2002 ◽  
Vol 38 ◽  
pp. 169-183 ◽  
Author(s):  
Graeme S Cottrell ◽  
Anne-Marie Coelho ◽  
Nigel W Bunnett
Keyword(s):  
Inflammatory Cells ◽  
Basic Mechanism ◽  
Extracellular Proteases ◽  
Protease Activated Receptors ◽  
Transcriptional Responses ◽  
Proteolytic Activation ◽  
Emergency Situations ◽  
Tethered Ligand ◽  
Single Use ◽  
G Protein Coupled

Certain extracellular proteases, derived from the circulation and inflammatory cells, can specifically cleave and trigger protease-activated receptors (PARs), a small, but important, sub-group of the G-protein-coupled receptor super-family. Four PARs have been cloned and they all share the same basic mechanism of activation: proteases cleave at a specific site within the extracellular N-terminus to expose a new N-terminal tethered ligand domain, which binds to and thereby activates the cleaved receptor. Thrombin activates PAR1, PAR3 and PAR4, trypsin activates PAR2 and PAR4, and mast cell tryptase activates PAR2 in this manner. Activated PARs couple to signalling cascades that affect cell shape, secretion, integrin activation, metabolic responses, transcriptional responses and cell motility. PARs are 'single-use' receptors: proteolytic activation is irreversible and the cleaved receptors are degraded in lysosomes. Thus, PARs play important roles in 'emergency situations', such as trauma and inflammation. The availability of selective agonists and antagonists of protease inhibitors and of genetic models has generated evidence to suggests that proteases and their receptors play important roles in coagulation, inflammation, pain, healing and protection. Therefore, selective antagonists or agonists of these receptors may be useful therapeutic agents for the treatment of human diseases.

Protease-activated receptor 2: activation, signalling and function

2003 ◽  
Vol 31 (6) ◽  
pp. 1191-1197 ◽  
Author(s):  
G.S. Cottrell ◽  
S. Amadesi ◽  
F. Schmidlin ◽  
N. Bunnett
Keyword(s):  
Inflammatory Cells ◽  
Coagulation Factors ◽  
G Protein Coupled Receptors ◽  
Protease Activated Receptors ◽  
Mitogen Activated Protein ◽  
Tethered Ligand ◽  
And Function ◽  
Protease Activated Receptor 2 ◽  
G Protein Coupled ◽  
Deficient Mice

PARs (protease-activated receptors) are a family of four G-protein-coupled receptors for proteases from the circulation, inflammatory cells and epithelial tissues. This report focuses on PAR2, which plays an important role in inflammation and pain. Pancreatic (trypsin I and II) and extrapancreatic (trypsin IV) trypsins, mast cell tryptase and coagulation factors VIIa and Xa cleave and activate PAR2. Proteases cleave PAR2 to expose a tethered ligand that binds to the cleaved receptor. Despite this irreversible activation, PAR2 signalling is attenuated by β-arrestin-mediated desensitization and endocytosis, and by lysosomal targeting and degradation, which requires ubiquitination of PAR2. β-Arrestins also act as scaffolds for the assembly of multi-protein signalling complexes that determine the location and function of activated mitogen-activated protein kinases. Observations of PAR2-deficient mice support a role for PAR2 in inflammation, and many of the effects of PAR2 activators promote inflammation. Inflammation is mediated in part by activation of PAR2 in the peripheral nervous system, which results in neurogenic inflammation and hyperalgesia.

scholarly journals Molecular Basis for G-protein-Coupled Receptor (GPCR) Activation and Biased Signalling at the Platelet Thrombin Receptor Proteinase Activated Receptor-4 (PAR4)

2019 ◽  
Author(s):  
Pierre E. Thibeault ◽  
Jordan C. LeSarge ◽  
D’Arcy Arends ◽  
Michaela Fernandes ◽  
Peter Chidiac ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
G Protein ◽  
Molecular Basis ◽  
Calcium Signalling ◽  
Cathepsin G ◽  
Mitogen Activated Protein Kinase ◽  
Proteolytic Activation ◽  
Gpcr Activation ◽  
Tethered Ligand ◽  
G Protein Coupled

AbstractProteinase Activated Receptor-4 (PAR4) is a member of the proteolytically-activated PAR family of G-Protein-coupled Receptors (GPCRs). PARs are activated following proteolytic cleavage of the receptor N-terminus by enzymes such as thrombin, trypsin, and cathepsin-G to reveal the receptor-activating motif termed the tethered ligand. The tethered ligand binds intramolecularly to the receptor and triggers receptor signalling and cellular responses. In spite of this unusual mechanism of activation, PARs are fundamentally peptide receptors and can also be activated by exogenous application of short synthetic peptides derived from the tethered ligand sequence. In order to gain a better understanding of the molecular basis for PAR4-dependent signalling, we examined signalling responses to a library of peptides derived from the canonical PAR4 activating peptide (PAR4-AP), AYPGKF-NH2. We examined peptide residues involved in activation of the Gαq/11-coupled calcium signalling pathway, β-arrestin recruitment, and mitogen-activated protein kinase pathway activation. The peptide N-methyl-alanine-YPGKF-NH2 was identified as a compound that is a poor activator of PAR4-dependent calcium signalling but was fully competent in recruiting β-arrestin-1 and -2. In order to gain a better understanding of the ligand-binding pocket, we used in silico docking to identify key residues involved in PAR4 interaction with AYPGKF-NH2. The predicted interactions were verified by site-directed mutagenesis and analysis of calcium signalling and β-arrestin-1/-2 recruitment following proteolytic activation (with thrombin) or activation with the synthetic agonist peptide (AYPGKF-NH2). We determined that a key extracellular loop-2 aspartic acid residue (Asp230) is critical for signalling following both proteolytic and peptide activation of PAR4. Finally, we investigated platelet aggregation in response to AyPGKF-NH2 (a peptide with D-tyrosine in position two) which is unable to activate calcium signalling, and AYPGRF-NH2 a peptide that is equipotent to the parental peptide AYPGKF-NH2 for calcium signalling but is more potent at recruiting β-arrestins. We found that AyPGKF-NH2 fails to activate platelets while AYPGRF-NH2 causes a platelet aggregation response that is greater than that seen with the parental peptide and is comparable to that seen with thrombin stimulation. Overall, these studies uncover molecular determinants for agonist binding and signalling through a non-canonically activated GPCR and provide a template for development of small molecule modulators of PAR4.

scholarly journals Protease Activated Receptors and Arthritis

2021 ◽  
Vol 22 (17) ◽  
pp. 9352
Author(s):  
Flora Lucena ◽  
Jason J. McDougall
Keyword(s):  
Serine Proteases ◽  
Vascular Reactivity ◽  
Structural Integrity ◽  
Therapeutic Potential ◽  
G Protein Coupled Receptors ◽  
Tissue Remodelling ◽  
Protease Activated Receptors ◽  
Tethered Ligand ◽  
Arthritic Joints ◽  
G Protein Coupled

The catabolic and destructive activity of serine proteases in arthritic joints is well known; however, these enzymes can also signal pain and inflammation in joints. For example, thrombin, trypsin, tryptase, and neutrophil elastase cleave the extracellular N-terminus of a family of G protein-coupled receptors and the remaining tethered ligand sequence then binds to the same receptor to initiate a series of molecular signalling processes. These protease activated receptors (PARs) pervade multiple tissues and cells throughout joints where they have the potential to regulate joint homeostasis. Overall, joint PARs contribute to pain, inflammation, and structural integrity by altering vascular reactivity, nociceptor sensitivity, and tissue remodelling. This review highlights the therapeutic potential of targeting PARs to alleviate the pain and destructive nature of elevated proteases in various arthritic conditions.

scholarly journals The Inflammatory Actions of Coagulant and Fibrinolytic Proteases in Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Michael Schuliga
Keyword(s):  
Transforming Growth Factor ◽  
Factor Viia ◽  
Degradation Products ◽  
Factor Xa ◽  
Inflammatory Cells ◽  
Bleeding Complications ◽  
Protease Activated Receptors ◽  
Proteolytic Activation ◽  
Fibrin Degradation Products ◽  
Mediators Of Inflammation

Aside from their role in hemostasis, coagulant and fibrinolytic proteases are important mediators of inflammation in diseases such as asthma, atherosclerosis, rheumatoid arthritis, and cancer. The blood circulating zymogens of these proteases enter damaged tissue as a consequence of vascular leak or rupture to become activated and contribute to extravascular coagulation or fibrinolysis. The coagulants, factor Xa (FXa), factor VIIa (FVIIa), tissue factor, and thrombin, also evoke cell-mediated actions on structural cells (e.g., fibroblasts and smooth muscle cells) or inflammatory cells (e.g., macrophages) via the proteolytic activation of protease-activated receptors (PARs). Plasmin, the principle enzymatic mediator of fibrinolysis, also forms toll-like receptor-4 (TLR-4) activating fibrin degradation products (FDPs) and can release latent-matrix bound growth factors such as transforming growth factor-β(TGF-β). Furthermore, the proteases that convert plasminogen into plasmin (e.g., urokinase plasminogen activator) evoke plasmin-independent proinflammatory actions involving coreceptor activation. Selectively targeting the receptor-mediated actions of hemostatic proteases is a strategy that may be used to treat inflammatory disease without the bleeding complications of conventional anticoagulant therapies. The mechanisms by which proteases of the coagulant and fibrinolytic systems contribute to extravascular inflammation in disease will be considered in this review.

scholarly journals Protease-Activated Receptors: Contribution to Physiology and Disease

2004 ◽  
Vol 84 (2) ◽  
pp. 579-621 ◽  
Author(s):  
VALERIA S. OSSOVSKAYA ◽  
NIGEL W. BUNNETT
Keyword(s):  
Protease Inhibitors ◽  
Serine Proteases ◽  
Inflammatory Cells ◽  
Coagulation Factors ◽  
Control Mechanisms ◽  
Physiological Control ◽  
Protease Activated Receptors ◽  
Future Challenges ◽  
Tethered Ligand ◽  
Selective Agonists

Ossovskaya, Valeria S., and Nigel W. Bunnett. Protease-Activated Receptors: Contribution to Physiology and Disease. Physiol Rev 84: 579–621, 2004; 10.1152/physrev.00028.2003.—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 facilitatehealing, 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.

scholarly journals Emerging Roles of Protease-Activated Receptors (PARs) in the Modulation of Synaptic Transmission and Plasticity

2021 ◽  
Vol 22 (2) ◽  
pp. 869
Author(s):  
Rachel Price ◽  
Nicola Biagio Mercuri ◽  
Ada Ledonne
Keyword(s):  
G Protein Coupled Receptors ◽  
Synaptic Efficacy ◽  
Protease Activated Receptors ◽  
Gabaergic Transmission ◽  
Cellular Survival ◽  
Physiological Conditions ◽  
Tethered Ligand ◽  
G Protein Coupled ◽  
The Brain ◽  
Unique Mechanism

Protease-activated receptors (PARs) are a class of G protein-coupled receptors (GPCRs) with a unique mechanism of activation, prompted by a proteolytic cleavage in their N-terminal domain that uncovers a tethered ligand, which binds and stimulates the same receptor. PARs subtypes (PAR1-4) have well-documented roles in coagulation, hemostasis, and inflammation, and have been deeply investigated for their function in cellular survival/degeneration, while their roles in the brain in physiological conditions remain less appreciated. Here, we describe PARs’ effects in the modulation of neurotransmission and synaptic plasticity. Available evidence, mainly concerning PAR1-mediated and PAR2-mediated regulation of glutamatergic and GABAergic transmission, supports that PARs are important modulators of synaptic efficacy and plasticity in normal conditions.

scholarly journals Protease-activated receptor signalling by coagulation proteases in endothelial cells

2014 ◽  
Vol 112 (11) ◽  
pp. 876-882 ◽  
Author(s):  
Alireza Rezaie
Keyword(s):  
Endothelial Cells ◽  
Vascular System ◽  
Activated Protein C ◽  
Integral Membrane Protein ◽  
Protease Activated Receptors ◽  
System A ◽  
Signalling Network ◽  
Protein Receptors ◽  
Activate Cell ◽  
G Protein Coupled

SummaryEndothelial cells express several types of integral membrane protein receptors, which upon interaction and activation by their specific ligands, initiate a signalling network that links extracellular cues in circulation to various biological processes within a plethora of cells in the vascular system. A small family of G-protein coupled receptors, termed protease-activated receptors (PAR1–4), can be specifically activated by coagulation proteases, thereby modulating a diverse array of cellular activities under various pathophysiological conditions. Thrombin and all vitamin K-dependent coagulation proteases, with the exception of factor IXa for which no PAR signalling has been attributed, can selectively activate cell surface PARs on the vasculature. Thrombin can activate PAR1, PAR3 and PAR4, but not PAR2 which can be specifically activated by factors VIIa and Xa. The mechanistic details of the specificity of PAR signalling by coagulation proteases are the subject of extensive investigation by many research groups worldwide. However, analysis of PAR signalling data in the literature has proved to be challenging since a single coagulation protease can elicit different signalling responses through activation of the same PAR receptor in endothelial cells. This article is focused on briefly reviewing the literature with respect to determinants of the specificity of PAR signalling by coagulation proteases with special emphasis on the mechanism of PAR1 signalling by thrombin and activated protein C in endothelial cells.

scholarly journals 5-Lipoxygenase Pathway, Dendritic Cells, and Adaptive Immunity

2004 ◽  
Vol 2004 (2) ◽  
pp. 99-105 ◽  
Author(s):  
Harizi Hedi ◽  
Gualde Norbert
Keyword(s):  
Dendritic Cells ◽  
Adaptive Immunity ◽  
Inflammatory Cells ◽  
Lipid Mediators ◽  
G Protein Coupled Receptors ◽  
Lipoxygenase Pathway ◽  
Innate And Adaptive Immunity ◽  
Paracrine Signalling ◽  
Signalling Molecules ◽  
G Protein Coupled

5-lipoxygenase (5-LO) pathway is the major source of potent proinflammatory leukotrienes (LTs) issued from the metabolism of arachidonic acid (AA), and best known for their roles in the pathogenesis of asthma. These lipid mediators are mainly released from myeloid cells and may act as physiological autocrine and paracrine signalling molecules, and play a central role in regulating the interaction between innate and adaptive immunity. The biological actions of LTs including their immunoregulatory and proinflammatory effects are mediated through extracellular specific G-protein-coupled receptors. Despite their role in inflammatory cells, such as neutrophils and macrophages, LTs may have important effects on dendritic cells (DC)-mediated adaptive immunity. Several lines of evidence show that DC not only are important source of LTs, but also become targets of their actions by producing other lipid mediators and proinflammatory molecules. This review focuses on advances in 5-LO pathway biology, the production of LTs from DC and their role on various cells of immune system and in adaptive immunity.

Anti-Chemokine Therapy for Inflammatory Diseases

2007 ◽  
Vol 20 (3) ◽  
pp. 447-453 ◽  
Author(s):  
M.L. Castellani ◽  
K. Bhattacharya ◽  
M. Tagen ◽  
D. Kempuraj ◽  
A. Perrella ◽  
...  
Keyword(s):  
Chemokine Receptors ◽  
Inflammatory Diseases ◽  
Heart Diseases ◽  
Diagnostic Procedures ◽  
Inflammatory Cells ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Clinical Scenarios ◽  
Inflammatory Proteins ◽  
G Protein Coupled

Chemokines are inflammatory proteins acting via G-protein coupled chemokine receptors that trigger different signaling pathways. Monocyte chemoattractant protein-1 (CCL2/MCP-1) and regulated on activation, normal T expressed and secreted (CCL5/RANTES) are the two major members of the CC chemokine beta subfamily. The roles of RANTES and MCP-1 are emerging in regulating the recruitment of inflammatory cells into tissue during inflammation. The inhibition of MCP-1 and RANTES with corresponding antibodies or other inhibitors may provide benefits in different clinical scenarios including cancer, inflammation, CNS disorders, parasitic disease, autoimmune and heart diseases. RANTES and MCP-1 may represent targets for diagnostic procedures and therapeutic intervention, and may be useful as a prognostic factor in the above diseases.

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