scholarly journals Proteinase-activated receptors in GtoPdb v.2021.3

2021 ◽  
Vol 2021 (3) ◽  
Author(s):  
Nigel Bunnett ◽  
Kathryn DeFea ◽  
Justin Hamilton ◽  
Morley D. Hollenberg ◽  
Rithwik Ramachandran ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Calcium Signalling ◽  
Airway Epithelial Cells ◽  
The Body ◽  
Cathepsin G ◽  
Airway Epithelial ◽  
Amino Terminal ◽  
Proteinase Activated Receptors ◽  
Tethered Ligand ◽  
The One

Proteinase-activated receptors (PARs, nomenclature as agreed by the NC-IUPHAR Subcommittee on Proteinase-activated Receptors [39]) are unique members of the GPCR superfamily activated by proteolytic cleavage of their amino terminal exodomains. Agonist proteinase-induced hydrolysis unmasks a tethered ligand (TL) at the exposed amino terminus, which acts intramolecularly at the binding site in the body of the receptor to effect transmembrane signalling. TL sequences at human PAR1-4 are SFLLRN-NH2, SLIGKV-NH2, TFRGAP-NH2 and GYPGQV-NH2, respectively. With the exception of PAR3, synthetic peptides with these sequences (as carboxyl terminal amides) are able to act as agonists at their respective receptors. Several proteinases, including neutrophil elastase, cathepsin G and chymotrypsin can have inhibitory effects at PAR1 and PAR2 such that they cleave the exodomain of the receptor without inducing activation of Gαq-coupled calcium signalling, thereby preventing activation by activating proteinases but not by agonist peptides. Neutrophil elastase (NE) cleavage of PAR1 and PAR2 can however activate MAP kinase signaling by exposing a TL that is different from the one revealed by trypsin [82]. PAR2 activation by NE regulates inflammation and pain responses [111, 72] and triggers mucin secretion from airway epithelial cells [112].

scholarly journals Proteinase-activated receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Nigel Bunnett ◽  
Kathryn DeFea ◽  
Justin Hamilton ◽  
Morley D. Hollenberg ◽  
Rithwik Ramachandran ◽  
...  
Keyword(s):  
Neutrophil Elastase ◽  
Calcium Signalling ◽  
Airway Epithelial Cells ◽  
The Body ◽  
Cathepsin G ◽  
Airway Epithelial ◽  
Amino Terminal ◽  
Proteinase Activated Receptors ◽  
Tethered Ligand ◽  
The One

Proteinase-activated receptors (PARs, nomenclature as agreed by the NC-IUPHAR Subcommittee on Proteinase-activated Receptors [35]) are unique members of the GPCR superfamily activated by proteolytic cleavage of their amino terminal exodomains. Agonist proteinase-induced hydrolysis unmasks a tethered ligand (TL) at the exposed amino terminus, which acts intramolecularly at the binding site in the body of the receptor to effect transmembrane signalling. TL sequences at human PAR1-4 are SFLLRN-NH2, SLIGKV-NH2, TFRGAP-NH2 and GYPGQV-NH2, respectively. With the exception of PAR3, synthetic peptides with these sequences (as carboxyl terminal amides) are able to act as agonists at their respective receptors. Several proteinases, including neutrophil elastase, cathepsin G and chymotrypsin can have inhibitory effects at PAR1 and PAR2 such that they cleave the exodomain of the receptor without inducing activation of Gαq-coupled calcium signalling, thereby preventing activation by activating proteinases but not by agonist peptides. Neutrophil elastase (NE) cleavage of PAR1 and PAR2 can however activate MAP kinase signaling by exposing a TL that is different from the one revealed by trypsin [73]. PAR2 ectivation by NE regulates inflammation and pain responses [101, 65] and triggers mucin secretion from airway epithelial cells [102].

Neutrophil elastase increases secretory leukocyte protease inhibitor transcript levels in airway epithelial cells

1993 ◽  
Vol 265 (3) ◽  
pp. L286-L292 ◽  
Author(s):  
J. M. Abbinante-Nissen ◽  
L. G. Simpson ◽  
G. D. Leikauf
Keyword(s):  
Epithelial Cells ◽  
Protease Inhibitor ◽  
Neutrophil Elastase ◽  
Airway Epithelial Cells ◽  
Secretory Leukocyte Protease Inhibitor ◽  
Cathepsin G ◽  
Dependent Manner ◽  
Airway Epithelial ◽  
Necrosis Factor Alpha ◽  
Transcript Levels

Airway inflammation is often associated with the infiltration of activated neutrophils and subsequent protease release. Although aiding in the digestion and phagocytosis of foreign proteins and microorganisms, neutrophil proteases can indiscriminately damage healthy lung tissue. In the conducting airway, proteases, particularly neutrophil elastase, are counter-balanced by several antiproteases, including secretory leukocyte protease inhibitor (SLPI). SLPI can be produced locally by a number of cells including the airway epithelial cell. To examine the effects of neutrophil granule components on SLPI transcript levels, airway epithelial cells were treated (up to 96 h) with elastase, other proteases, or enzymes isolated from human sputum. We found that neutrophil elastase increased SLPI transcript levels in primary and transformed human airway epithelial cells in a time- and dose-dependent manner. Other neutrophil products, such as cathepsin G, myeloperoxidase, and lysozyme, had little or no effect on SLPI transcript levels. However, two nonneutrophil proteases, trypsin and pancreatic elastase, also increased SLPI transcript levels at higher doses than that required of neutrophil elastase. Two inflammatory cytokines, tumor necrosis factor-alpha and interleukin-8, produced little or no effect on SLPI transcript levels. This study demonstrates one way in which SLPI is regulated, via a protease that it inhibits, neutrophil elastase.

Effect of defensins on interleukin-8 synthesis in airway epithelial cells

1997 ◽  
Vol 272 (5) ◽  
pp. L888-L896 ◽  
Author(s):  
S. Van Wetering ◽  
S. P. Mannesse-Lazeroms ◽  
M. A. Van Sterkenburg ◽  
M. R. Daha ◽  
J. H. Dijkman ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Neutrophil Elastase ◽  
Proteinase Inhibitor ◽  
De Novo ◽  
Tissue Injury ◽  
A549 Cells ◽  
Airway Epithelial Cells ◽  
Epithelial Cell Line ◽  
Mrna Levels ◽  
Airway Epithelial

Neutrophils play an important role in inflammatory processes in the lung and may cause tissue injury through, for example, release of proteinases such as neutrophil elastase. In addition to neutrophil elastase, stimulated neutrophils also release small nonenzymatic and cationic polypeptides termed defensins. The aim of the present study was to investigate whether defensins induce interleukin (IL)-8 expression in cells of the A549 lung epithelial cell line and in human primary bronchial epithelial cells (PBEC). Supernatants of defensin-treated A549 cells contained increased neutrophil chemotactic activity (16-fold) that was inhibited by antibodies against IL-8. Concurrently, within 3 and 6 h, defensins significantly increased the IL-8 levels in supernatants of both A549 cells (n = 6, P < 0.05 and P < 0.01, respectively) and PBEC (n = 4, P < 0.001 and P < 0.001, respectively). This defensin-induced increase was fully inhibited by the serine proteinase inhibitor alpha 1-proteinase inhibitor. In addition, defensins also increased IL-8 mRNA levels (12-fold); this increase was dependent on de novo mRNA synthesis and did not require protein synthesis. Furthermore, defensins did not affect IL-8 mRNA stability, indicating that the enhanced IL-8 expression was due to increased transcription. Our findings suggest that defensins, released by stimulated neutrophils, stimulate IL-8 synthesis by airway epithelial cells and thus may mediate the recruitment of additional neutrophils into the airways.

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.

Activation and damage of cultured airway epithelial cells by human elastase and cathepsin G

1992 ◽  
Vol 228 (4) ◽  
pp. 213-218 ◽  
Author(s):  
Marie-Anne Nahori ◽  
Patricia Renesto ◽  
B.Boris Vargaftig ◽  
Michel Chignard
Keyword(s):  
Epithelial Cells ◽  
Airway Epithelial Cells ◽  
Cathepsin G ◽  
Airway Epithelial

scholarly journals Mycobacteria Manipulate G-Protein-Coupled Receptors to Increase Mucosal Rac1 Expression in the Lungs

2016 ◽  
Vol 9 (3) ◽  
pp. 318-329 ◽  
Author(s):  
Nader Alaridah ◽  
Nataliya Lutay ◽  
Erik Tenland ◽  
Anna Rönnholm ◽  
Oskar Hallgren ◽  
...  
Keyword(s):  
G Protein ◽  
Airway Epithelial Cells ◽  
G Protein Coupled Receptors ◽  
The Body ◽  
Airway Epithelial ◽  
Mucosal Vaccination ◽  
Mapk Signalling Pathway ◽  
The Impact ◽  
G Protein Coupled ◽  
Rac1 Expression

Mycobacterium bovis bacille Calmette-Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB). BCG mimics M. tuberculosis (Mtb) in its persistence in the body and is used as a benchmark to compare new vaccine candidates. BCG was originally designed for mucosal vaccination, but comprehensive knowledge about its interaction with epithelium is currently lacking. We used primary airway epithelial cells (AECs) and a murine model to investigate the initial events of mucosal BCG interactions. Furthermore, we analysed the impact of the G-protein-coupled receptors (GPCRs), CXCR1 and CXCR2, in this process, as these receptors were previously shown to be important during TB infection. BCG infection of AECs induced GPCR-dependent Rac1 up-regulation, resulting in actin redistribution. The altered distribution of the actin cytoskeleton involved the MAPK signalling pathway. Blocking of the CXCR1 or CXCR2 prior to infection decreased Rac1 expression, and increased epithelial transcriptional activity and epithelial cytokine production. BCG infection did not result in epithelial cell death as measured by p53 phosphorylation and annexin. This study demonstrated that BCG infection of AECs manipulated the GPCRs to suppress epithelial signalling pathways. Future vaccine strategies could thus be improved by targeting GPCRs.

scholarly journals Epithelial Immunomodulation by Aerosolized Toll-like Receptor Agonists Attenuates Allergic Responsiveness in Mice

2021 ◽  
Author(s):  
David L Goldblatt ◽  
Gabriella Valverde Ha ◽  
Shradha Wali ◽  
Vikram V Kulkarni ◽  
Michael K Longmire ◽  
...  
Keyword(s):  
Immune Response ◽  
Epithelial Cells ◽  
Allergen Immunotherapy ◽  
Airway Remodeling ◽  
Allergic Sensitization ◽  
Airway Epithelial Cells ◽  
The Body ◽  
Immunomodulatory Effect ◽  
Airway Epithelial ◽  
Receptor Agonists

Allergic asthma is a chronic inflammatory respiratory disease associated with eosinophilic infiltration, increased mucus production, airway hyperresponsiveness (AHR), and airway remodeling. Epidemiologic data has revealed that the prevalence of allergic sensitization and associated diseases has increased in the twentieth century. This has been hypothesized to be partly due to reduced contact with microbial organisms (the hygiene hypothesis) in industrialized society. Airway epithelial cells, once considered a static physical barrier between the body and the external world, are now widely recognized as immunologically active cells that can initiate, maintain, and restrain inflammatory responses, such as those that mediate allergic disease. Airway epithelial cells can sense allergens via myriad expression of Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs). We sought to determine whether the innate immune response stimulated by a combination of Pam2CSK4 ('Pam2', TLR2/6 ligand) and a class C oligodeoxynucleotide ODN362 ('ODN', TLR9 ligand) when delivered together by aerosol ('Pam2ODN'), can modulate the allergic immune response to allergens. Treatment with Pam2ODN 7 days before sensitization to House Dust Mite (HDM) extract resulted in a strong reduction in eosinophilic and lymphocytic inflammation. This Pam2ODN immunomodulatory effect was also seen using Ovalbumin (OVA) and A. oryzae mouse models. The immunomodulatory effect was observed as much as 30 days before sensitization to HDM, but ineffective just 2 days after sensitization, suggesting that Pam2ODN mechanism of action involves immunomodulation of the response from airway epithelial cells to aeroallergens, possibly due to a repolarization of the immune response from type 2 to a type 3/type 17 direction. Furthermore, Pam2 and ODN cooperated synergistically to induce the immunomodulatory phenotype suggesting that this treatment is superior to all investigational TLR receptor agonists in the allergen immunotherapy setting which only utilize a single PRR agonist at one time. These data suggest that allergen immunotherapy using Pam2ODN might have a role in maximizing allergen immunotherapy effectiveness.

Cystic fibrosis affects chloride and sodium channels in human airway epithelia

1989 ◽  
Vol 67 (10) ◽  
pp. 1362-1365 ◽  
Author(s):  
Marek Duszyk ◽  
Andrew S. French ◽  
S. F. Paul Man
Keyword(s):  
Cystic Fibrosis ◽  
Sodium Channels ◽  
Chloride Channels ◽  
Genetic Defect ◽  
Airway Epithelial Cells ◽  
Cell Membrane Permeability ◽  
Single Type ◽  
Airway Epithelial ◽  
Patch Clamp Technique ◽  
The One

Abnormalities of epithelial function in cystic fibrosis (CF) have been linked to defects in cell membrane permeability to chloride or sodium ions. Recently, a class of chloride channels in airway epithelial cells have been reported to lack their usual sensitivity to phosphorylation via cAMP-dependent protein kinase, suggesting that CF could be due to a single genetic defect in these channels. We have examined single chloride and sodium channels in control and CF human nasal epithelia using the patch-clamp technique. The most common chloride channel was not the one previously associated with CF, but it was also abnormal in CF cells. In addition, the number of sodium channels was unusually high in CF. These findings suggest a wider disturbance of ion channel properties in CF than would be produced by a defect in a single type of channel.Key words: ion channels, cystic fibrosis, airway, epithelium.

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