ArticleThe Journal of biological chemistry2015
Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 103 papers.
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Who cites it
103 citing papers in PubMed, 165 citations in OpenAlex.
- From Inflammation to Neuroplasticity: Molecular Mechanisms of Pain in Acute, Recurrent and Chronic Pancreatitis.International journal of molecular sciences · 2026Review
- Epigenetic Regulation of the NET Formation-Blood-Brain Barrier Axis in Ischemic Stroke: Mechanisms, Therapeutic Targets and Translational Perspectives.Neurology international · 2026Review
- Monoclonal antibody inhibition of PAR2 reduces phenotype severity and pain in murine inflammatory bowel disease.Pain reports · 2026Article
- MMP1 and PRSS23 induce PARCommunications biology · 2026Article
- Protease-Activated Receptor-2 Promotes Metastasis: An Emerging Therapeutic Target.Molecular cancer research : MCR · 2026Review
- Protease-activated receptors act as a liaison between metabolism and inflammation.Inflammopharmacology · 2026Review
- Modulation of Nociceptive Ion Channels by Protease-Activated Receptor-2 in Inflammatory Pain: Molecular Mechanisms and Therapeutic Potential.International journal of molecular sciences · 2026Review
- MASSAG model: Towards an integrative neuroscience framework linking emotional trauma, pain, and mechanisms of force-based manipulations.Neuroscience and biobehavioral reviews · 2026Review
- Electrophysiological and Proteomic Evidence of Protease-Mediated Pro-nociceptive Signaling in Inflammatory Bowel Disease Patients.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Trypsin inhibitor isolated from the seeds of Inga laurina (sw.) Willd decreased inflammatory and nociceptive responses in mice.Inflammopharmacology · 2025Article
- Research progress of TRPV4 in pain over the past 20 years: a bibliometric analysis.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Article
- A major Toxoplasma serine protease inhibitor protects the parasite against gut-derived serine proteases and NETosis damage.The Journal of biological chemistry · 2025Article
- Neutrophil Elastase and Elafin in Inflammatory Bowel Diseases: Urinary Biomarkers Reflecting Intestinal Barrier Dysfunction and Proteolytic Activity.Journal of clinical medicine · 2025Article
- TRPV4 Channel in Neurological Disease: from Molecular Mechanisms to Therapeutic Potential.Molecular neurobiology · 2025Review
- A QUARTER CENTURY OF CALCIUM-PERMEABLE ION CHANNEL, TRPV4: PERSPECTIVES ON EXPRESSION AND FUNCTION IN ENDOTHELIAL CELLS-TIME TO TRANSLATE.Transactions of the American Clinical and Climatological Association · 2025Review
- Neutrophils in Atopic Dermatitis.Clinical reviews in allergy & immunology · 2024Review
- Extracellular Vesicle-Associated Neutrophil Elastase Activates Hepatic Stellate Cells and Promotes Liver Fibrogenesis via ERK1/2 Pathway.bioRxiv : the preprint server for biology · 2024Article
- Targeting TRPV4 Channels for Cancer Pain Relief.Cancers · 2024Review
- Neutrophils in Inflammatory Bone Diseases.Current osteoporosis reports · 2024Review
43 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 4 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Proteases that cleave protease-activated receptor-2 (PAR(2)) at Arg(36)↓Ser(37) reveal a tethered ligand that binds to the cleaved receptor. PAR(2) activates transient receptor potential (TRP) channels of nociceptive neurons to induce neurogenic inflammation and pain. Although proteases that cleave PAR(2) at non-canonical sites can trigger distinct signaling cascades, the functional importance of the PAR(2)-biased agonism is uncertain. We investigated whether neutrophil elastase, a biased agonist of PAR(2), causes inflammation and pain by activating PAR2 and TRP vanilloid 4 (TRPV4). Elastase cleaved human PAR(2) at Ala(66)↓Ser(67) and Ser(67)↓Val(68). Elastase stimulated PAR(2)-dependent cAMP accumulation and ERK1/2 activation, but not Ca(2+) mobilization, in KNRK cells. Elastase induced PAR(2) coupling to Gαs but not Gαq in HEK293 cells. Although elastase did not promote recruitment of G protein-coupled receptor kinase-2 (GRK(2)) or β-arrestin to PAR(2), consistent with its inability to promote receptor endocytosis, elastase did stimulate GRK6 recruitment. Elastase caused PAR(2)-dependent sensitization of TRPV4 currents in Xenopus laevis oocytes by adenylyl cyclase- and protein kinase A (PKA)-dependent mechanisms. Elastase stimulated PAR(2)-dependent cAMP formation and ERK1/2 phosphorylation, and a PAR(2)- and TRPV4-mediated influx of extracellular Ca(2+) in mouse nociceptors. Adenylyl cyclase and PKA-mediated elastase-induced activation of TRPV4 and hyperexcitability of nociceptors. Intraplantar injection of elastase to mice caused edema and mechanical hyperalgesia by PAR(2)- and TRPV4-mediated mechanisms. Thus, the elastase-biased agonism of PAR(2) causes Gαs-dependent activation of adenylyl cyclase and PKA, which activates TRPV4 and sensitizes nociceptors to cause inflammation and pain. Our results identify a novel mechanism of elastase-induced activation of TRPV4 and expand the role of PAR(2) as a mediator of protease-driven inflammation and pain.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.