ArticleThe Journal of physiology2007
Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice.
Article in The Journal of physiology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 202 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
202 citing papers in PubMed, 1 synthesis or guideline pooled it, 386 citations in OpenAlex.
- Mechanosensitive receptors in migraine: a systematic review.The journal of headache and pain · 2024Pooled it
- 25+ Years of TRPV4: From Discovery to Translational Horizons.Research square · 2026Article
- MMP1 and PRSS23 induce PARCommunications biology · 2026Article
- The Mast Cell-PAR2-TRP Axis: A Convergent Mechanism for Visceral Hypersensitivity Independent of Divergent Motility in IBS.Biomolecules · 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
- Hereditary α-tryptasemia; a review of mechanisms linking α-tryptase gene dosage to intestinal homeostasis and immunopathology.Frontiers in allergy · 2026Review
- Research Progress on Upper Airway Cough Syndrome.World journal of otorhinolaryngology - head and neck surgery · 2025Review
- A Bacteroides fragilis protease activates host PARCell host & microbe · 2025Article
- Research progress of TRPV4 in pain over the past 20 years: a bibliometric analysis.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Efficacy of MEDI0618, a pH-dependent monoclonal antibody targeting PAR2, in preclinical models of migraine.Brain : a journal of neurology · 2025Article
- PAR2 Participates in the Development of Cough Hypersensitivity in Guinea Pigs by Regulating TRPA1 Through PKC.Biomolecules · 2025Article
- 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
- Tuina Alleviates Neuropathic Pain in CCI Rats by Regulating the TRPV4-CaMKII Signaling Pathway in Dorsal Root Ganglion.Pain research & management · 2025Article
- Neuromodulators in Acute and Chronic Cough in Children: An Update from the Literature.International journal of molecular sciences · 2024Review
- Mast cell modulation: A novel therapeutic strategy for abdominal pain in irritable bowel syndrome.Cell reports. Medicine · 2024Review
- The Role of the TRPV4 Channel in Intestinal Physiology and Pathology.Journal of inflammation research · 2024Review
- Protease-Activated Receptor 2 (PAR2) Expressed in Sensory Neurons Contributes to Signs of Pain and Neuropathy in Paclitaxel Treated Mice.The journal of pain · 2023Article
- Targeting Nociceptive Neurons and Transient Receptor Potential Channels for the Treatment of Migraine.International journal of molecular sciences · 2023Review
- Antagonism of TRPV4 channels partially reduces mechanotransduction in rat skeletal muscle afferents.The Journal of physiology · 2023Article
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
142 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 6 institutions in 4 countries.
Funding
Abstract
Exacerbated sensitivity to mechanical stimuli that are normally innocuous or mildly painful (mechanical allodynia and hyperalgesia) occurs during inflammation and underlies painful diseases. Proteases that are generated during inflammation and disease cleave protease-activated receptor 2 (PAR2) on afferent nerves to cause mechanical hyperalgesia in the skin and intestine by unknown mechanisms. We hypothesized that PAR2-mediated mechanical hyperalgesia requires sensitization of the ion channel transient receptor potential vanilloid 4 (TRPV4). Immunoreactive TRPV4 was coexpressed by rat dorsal root ganglia (DRG) neurons with PAR2, substance P (SP) and calcitonin gene-related peptide (CGRP), mediators of pain transmission. In PAR2-expressing cell lines that either naturally expressed TRPV4 (bronchial epithelial cells) or that were transfected to express TRPV4 (HEK cells), pretreatment with a PAR2 agonist enhanced Ca2+ and current responses to the TRPV4 agonists phorbol ester 4alpha-phorbol 12,13-didecanoate (4alphaPDD) and hypotonic solutions. PAR2-agonist similarly sensitized TRPV4 Ca2+ signals and currents in DRG neurons. Antagonists of phospholipase Cbeta and protein kinases A, C and D inhibited PAR2-induced sensitization of TRPV4 Ca2+ signals and currents. 4alphaPDD and hypotonic solutions stimulated SP and CGRP release from dorsal horn of rat spinal cord, and pretreatment with PAR2 agonist sensitized TRPV4-dependent peptide release. Intraplantar injection of PAR2 agonist caused mechanical hyperalgesia in mice and sensitized pain responses to the TRPV4 agonists 4alphaPDD and hypotonic solutions. Deletion of TRPV4 prevented PAR2 agonist-induced mechanical hyperalgesia and sensitization. This novel mechanism, by which PAR2 activates a second messenger to sensitize TRPV4-dependent release of nociceptive peptides and induce mechanical hyperalgesia, may underlie inflammatory hyperalgesia in diseases where proteases are activated and released.
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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.