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 Evaluation on Potential Contributions of Protease Activated Receptors Related Mediators in Allergic Inflammation

2014 ◽  
Vol 2014 ◽  
pp. 1-20 ◽  
Author(s):  
Huiyun Zhang ◽  
Xiaoning Zeng ◽  
Shaoheng He
Keyword(s):  
Serine Proteases ◽  
Inflammatory Cell ◽  
Allergic Inflammation ◽  
G Protein Coupled Receptors ◽  
Cell Behavior ◽  
Protease Activated Receptors ◽  
Pathologic Process ◽  
Allergic Disorders ◽  
G Protein Coupled

Protease activated receptors (PARs) have been recognized as a distinctive four-member family of seven transmembrane G protein-coupled receptors (GPCRs) that can be cleaved by certain serine proteases. In recent years, there has been considerable interest in the role of PARs in allergic inflammation, the fundamental pathologic changes of allergy, but the potential roles of PARs in allergy remain obscure. Since many of these proteases are produced and actively involved in the pathologic process of inflammation including exudation of plasma components, inflammatory cell infiltration, and tissue damage and repair, PARs appear to make important contribution to allergy. The aim of the present review is to summarize the expression of PARs in inflammatory and structural cells, the influence of agonists or antagonists of PARs on cell behavior, and the involvement of PARs in allergic disorders, which will help us to better understand the roles of serine proteases and PARs in allergy.

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.

Proteinase-activated receptors: novel mechanisms of signaling by serine proteases

1998 ◽  
Vol 274 (6) ◽  
pp. C1429-C1452 ◽  
Author(s):  
Olivier Déry ◽  
Carlos U. Corvera ◽  
Martin Steinhoff ◽  
Nigel W. Bunnett
Keyword(s):  
G Proteins ◽  
Serine Proteases ◽  
G Protein Coupled Receptors ◽  
Parallel Mechanisms ◽  
New Family ◽  
Proteinase Activated Receptors ◽  
Degradative Enzymes ◽  
Tethered Ligand ◽  
G Protein Coupled ◽  
Efficient Mechanisms

Although serine proteases are usually considered to act principally as degradative enzymes, certain proteases are signaling molecules that specifically regulate cells by cleaving and triggering members of a new family of proteinase-activated receptors (PARs). There are three members of this family, PAR-1 and PAR-3, which are receptors for thrombin, and PAR-2, a receptor for trypsin and mast cell tryptase. Proteases cleave within the extracellular NH2-terminus of their receptors to expose a new NH2-terminus. Specific residues within this tethered ligand domain interact with extracellular domains of the cleaved receptor, resulting in activation. In common with many G protein-coupled receptors, PARs couple to multiple G proteins and thereby activate many parallel mechanisms of signal transduction. PARs are expressed in multiple tissues by a wide variety of cells, where they are involved in several pathophysiological processes, including growth and development, mitogenesis, and inflammation. Because the cleaved receptor is physically coupled to its agonist, efficient mechanisms exist to terminate signaling and prevent uncontrolled stimulation. These include cleavage of the tethered ligand, receptor phosphorylation and uncoupling from G proteins, and endocytosis and lysosomal degradation of activated receptors.

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 receptors in kidney disease progression

2016 ◽  
Vol 311 (6) ◽  
pp. F1140-F1144 ◽  
Author(s):  
Oleg Palygin ◽  
Daria V. Ilatovskaya ◽  
Alexander Staruschenko
Keyword(s):  
Disease Progression ◽  
Serine Proteases ◽  
Mesangial Cells ◽  
Protease Activated Receptors ◽  
Renal Disease Progression ◽  
Protease Cleavage ◽  
Tethered Ligand ◽  
Kidney Disease Progression ◽  
Inflammatory Regulation ◽  
Functional Mechanisms

Protease-activated receptors (PARs) are members of a well-known family of transmembrane G protein-coupled receptors (GPCRs). Four PARs have been identified to date, of which PAR1 and PAR2 are the most abundant receptors, and have been shown to be expressed in the kidney vascular and tubular cells. PAR signaling is mediated by an N-terminus tethered ligand that can be unmasked by serine protease cleavage. The receptors are activated by endogenous serine proteases, such as thrombin (acts on PARs 1, 3, and 4) and trypsin (PAR2). PARs can be involved in glomerular, microvascular, and inflammatory regulation of renal function in both normal and pathological conditions. As an example, it was shown that human glomerular epithelial and mesangial cells express PARs, and these receptors are involved in the pathogenesis of crescentic glomerulonephritis, glomerular fibrin deposition, and macrophage infiltration. Activation of these receptors in the kidney also modulates renal hemodynamics and glomerular filtration rate. Clinical studies further demonstrated that the concentration of urinary thrombin is associated with glomerulonephritis and type 2 diabetic nephropathy; thus, molecular and functional mechanisms of PARs activation can be directly involved in renal disease progression. We briefly discuss here the recent literature related to activation of PAR signaling in glomeruli and the kidney in general and provide some examples of PAR1 signaling in glomeruli podocytes.

scholarly journals Pan-cancer in silico analysis of somatic mutations in G-protein coupled receptors: The effect of evolutionary conservation and natural variance

2021 ◽  
Author(s):  
Brandon J Bongers ◽  
Marina Gorostiola González ◽  
Xuesong Wang ◽  
Herman WT van Vlijmen ◽  
Willem Jespers ◽  
...  
Keyword(s):  
G Protein ◽  
Structural Integrity ◽  
In Silico Analysis ◽  
G Protein Coupled Receptors ◽  
Dry Motif ◽  
Synthetic Ligand ◽  
Natural Variance ◽  
G Protein Coupled ◽  
Pan Cancer

G protein-coupled receptors (GPCRs) form the most frequently exploited drug target family, moreover they are often found mutated in cancer. Here we used an aggregated dataset of mutations found in cancer patient samples derived from the Genomic Data Commons and compared it to the natural human variance as exemplified by data from the 1000 Genomes project. While the location of these mutations across the protein domains did not differ significantly in the two datasets, a mutation enrichment was observed in cancer patients among conserved residues in GPCRs such as the 'DRY' motif. We subsequently created a ranking of high scoring GPCRs, using a multi-objective approach (Pareto Front Ranking). The validity of our approach was confirmed by re-discovery of established cancer targets such as the LPA and mGlu receptor families, and we identified novel GPCRs that had not been directly linked to cancer before such as the P2Y Receptor 10 (P2RY10). As a proof of concept, we projected the structurally investigated mutations in the crystal structure of the C-C Chemokine (CCR) 5 receptor, one of the high-ranking GPCRs previously linked to cancer. Several positions were pinpointed that relate to either structural integrity or endogenous and synthetic ligand binding, providing a rationale to their mechanism of influence in cancer. In conclusion, this study identifies a list of GPCRs that are prioritized for experimental follow up characterization to elucidate their role in cancer. The computational approach here described can be adapted to investigate the roles in cancer of any protein family.

Challenges in Design and Development of PAR Inhibitors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-45-SCI-45
Author(s):  
Patricia Andrade-Gordon
Keyword(s):  
Drug Target ◽  
Human Platelet ◽  
Bleeding Risk ◽  
G Protein Coupled Receptors ◽  
Protease Activated Receptors ◽  
Small Molecule Antagonist ◽  
Clinical Benefits ◽  
Platelet Aggregates ◽  
G Protein Coupled ◽  
Sustained Activation

Abstract Abstract SCI-45 Inappropriate and sustained activation of platelets is a major cause of vascular occlusive diseases such as angina, myocardial infarction, and stroke. The development of thrombi within blood vessels results from the formation of platelet aggregates and fibrin deposits, and heavily depends on the actions of α-thrombin. It is now well recognized that human platelet responses to α-thrombin are mediated by the protease-activated receptors PAR1 and PAR4. Protease-activated receptors (PARs) represent a unique family of seven-transmembrane G-protein-coupled receptors, which are enzymatically cleaved to expose a new extracellular N-terminus that acts as a “tethered” activating ligand. Since the discovery of PAR1 as the major contributor to human platelet aggregation, there has been a keen interest to develop antagonist as potential antithrombotics. However, there have been many issues and challenges in this endeavor. One crucial challenge to the discovery of potent antagonists is the strong entropy advantage offered by the intramolecular binding mechanism of PARs activation, which presents a great disadvantage to a circulating small molecule antagonist. To be an effective therapeutic agent, a PAR1 antagonist not only should bind tightly to the receptor but also possess suitable binding kinetics. Another issue for the discovery of PAR1 antagonists is the preclinical logistics associated with species variability of PAR1 on platelets. Despite these challenges, PAR1 has been an attractive drug target and there has been considerable activity and progress in the discovery and development of PAR1 antagonist as therapeutic agents. The promise of these novel therapeutics is reflected by two antiplatelet PAR1 antagonists in advanced clinical trials. The clinical benefits derived from these agents will be determined by the tight balance between delivering efficacy in the context of thrombotic disease and controlling the bleeding risk. The discussion will focus on the challenges from discovery to development of these great potential opportunities in the prevention of atherothrombotic disease. Disclosures: Andrade-Gordon: Johnson & Johnson: Employment.

scholarly journals The evolution and mechanism of GPCR proton sensing

2020 ◽  
pp. jbc.RA120.016352
Author(s):  
Jacob B. Rowe ◽  
Nicholas J. Kapolka ◽  
Geoffrey J. Taghon ◽  
William M. Morgan ◽  
Daniel G. Isom
Keyword(s):  
Therapeutic Potential ◽  
G Protein Coupled Receptors ◽  
Hek293 Cells ◽  
Ph Sensing ◽  
Physiological Importance ◽  
Class A ◽  
Acidic Residues ◽  
Ph Range ◽  
G Protein Coupled ◽  
Direct Regulation

Of the 800 G protein-coupled receptors (GPCRs) in humans, only three (GPR4, GPR65, and GPR68) regulate signaling in acidified microenvironments by sensing protons (H+). How these receptors have uniquely obtained this ability is unknown. Here we show these receptors evolved the capability to sense H+ signals by acquiring buried acidic residues. Using our informatics platform pHinder, we identified a triad of buried acidic residues shared by all three receptors, a feature distinct from all other human GPCRs. Phylogenetic analysis shows the triad emerged in GPR65, the immediate ancestor of GPR4 and GPR68. To understand the evolutionary and mechanistic importance of these triad residues, we developed Deep Variant Profiling (DVP), a yeast-based technology that utilizes high-throughput CRISPR to build and profile large libraries of GPCR variants. Using DVP and GPCR assays in HEK293 cells, we assessed the pH-sensing contributions of each triad residue in all three receptors. As predicted by our calculations, most triad mutations had profound effects consistent with direct regulation of receptor pH sensing. Additionally, we found that an allosteric modulator of many class A GPCRs, Na+, synergistically regulated pH sensing by maintaining the pKa values of triad residues within the physiologically relevant pH range. As such, we show that all three receptors function as coincidence detectors of H+ and Na+. Taken together, these findings elucidate the molecular evolution and long-sought mechanism of GPR4, GPR65, and GPR68 pH sensing, and provide pH-insensitive variants that should be valuable for assessing the therapeutic potential and (patho)physiological importance of GPCR pH sensing.

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