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 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 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.

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.

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 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.

scholarly journals Sphingosine 1-phosphate signalling through the G-protein-coupled receptor Edg-1

1998 ◽  
Vol 330 (2) ◽  
pp. 605-609 ◽  
Author(s):  
C. M. Gerben ZONDAG ◽  
R. Friso POSTMA ◽  
Ingrid VAN ETTEN ◽  
Ingrid VERLAAN ◽  
H. Wouter MOOLENAAR
Keyword(s):  
Adenylate Cyclase ◽  
Map Kinase ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Lpa Receptor ◽  
Kinase Activation ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Sphingosine 1 Phosphate ◽  
G Protein Coupled

Sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) are structurally related lipid mediators that act on distinct G-protein-coupled receptors to evoke similar responses, including Ca2+ mobilization, adenylate cyclase inhibition, and mitogen-activated protein (MAP) kinase activation. However, little is still known about the respective receptors. A recently cloned putative LPA receptor (Vzg-1/Edg-2) is similar to an orphan Gi-coupled receptor termed Edg-1. Here we show that expression of Edg-1 in Sf9 and COS-7 cells results in inhibition of adenylate cyclase and activation of MAP kinase (Gi-mediated), but not Ca2+ mobilization, in response to S1P. These responses are specific in that (i) S1P action is not mimicked by LPA, and (ii) Vzg-1/Edg-2 cannot substitute for Edg-1. Thus the Edg-1 receptor is capable of mediating a subset of the cellular responses to S1P.

scholarly journals Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies

2020 ◽  
Vol 21 (23) ◽  
pp. 9203
Author(s):  
Renée Daams ◽  
Ramin Massoumi
Keyword(s):  
Tissue Homeostasis ◽  
Spinocerebellar Ataxias ◽  
Adult Tissue ◽  
Signalling Molecules ◽  
Cellular Processes ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
And Function ◽  
Deficient Mice

The Wnt signalling pathway is a central communication cascade between cells to orchestrate polarity and fate during development and adult tissue homeostasis in various organisms. This pathway can be regulated by different signalling molecules in several steps. One of the coordinators in this pathway is Nemo-like kinase (NLK), which is an atypical proline-directed serine/threonine mitogen-activated protein (MAP) kinase. Very recently, NLK was established as an essential regulator in different cellular processes and abnormal NLK expression was highlighted to affect the development and progression of various diseases. In this review, we focused on the recent discoveries by using NLK-deficient mice, which show a phenotype in the development and function of organs such as the lung, heart and skeleton. Furthermore, NLK could conduct the function and differentiation of cells from the immune system, in addition to regulating neurodegenerative diseases, such as Huntington’s disease and spinocerebellar ataxias. Overall, generations of NLK-deficient mice have taught us valuable lessons about the role of this kinase in certain diseases and development.

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