ArticleThe Journal of biological chemistry2013
Protease-activated receptor 2 (PAR2) protein and transient receptor potential vanilloid 4 (TRPV4) protein coupling is required for sustained inflammatory signaling.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 94 papers.
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Who cites it
94 citing papers in PubMed, 160 citations in OpenAlex.
- An update on regulation of the polymodal TRPV4 channel by protein phosphorylation.Channels (Austin, Tex.) · 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
- 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
- Endosomal MrGPRX1 signaling sensitizes TRPV1 to enhance itch.Frontiers in molecular neuroscience · 2026Article
- Microbial sensing through the non-canonical inflammasome modulates airway type 2 immunity.Frontiers in immunology · 2026Article
- Endosomal MrGPRX1 signaling sensitizes TRPV1 to enhance itch.bioRxiv : the preprint server for biology · 2025Article
- Neuromodulators in Acute and Chronic Cough in Children: An Update from the Literature.International journal of molecular sciences · 2024Review
- Beyond Anticoagulation: A Comprehensive Review of Non-Vitamin K Oral Anticoagulants (NOACs) in Inflammation and Protease-Activated Receptor Signaling.International journal of molecular sciences · 2024Review
- The Role of TRP Channels in Sepsis and Colitis.International journal of molecular sciences · 2024Review
- Multifactorial Causes and Consequences of TLSP Production, Function, and Release in the Asthmatic Airway.Biomolecules · 2024Review
- TRPV4 is expressed by enteric glia and muscularis macrophages of the colon but does not play a prominent role in colonic motility.bioRxiv : the preprint server for biology · 2024Article
- The Role of the TRPV4 Channel in Intestinal Physiology and Pathology.Journal of inflammation research · 2024Review
- Hyperoside ameliorates cerebral ischaemic-reperfusion injury by opening the TRPV4 channelPharmaceutical biology · 2023Article
- Article
- 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
- Inflammation, lipids, and pain in vulvar disease.Pharmacology & therapeutics · 2023Review
- Endothelial PAR2 activation evokes resistance artery relaxation.Journal of cellular physiology · 2023Article
- Molecular Mechanisms of Neurogenic Inflammation of the Skin.International journal of molecular sciences · 2023Review
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
- TRP Channels: Recent Development in Translational Research and Potential Therapeutic Targets in Migraine.International journal of molecular sciences · 2022Review
34 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
Abstract
G protein-coupled receptors of nociceptive neurons can sensitize transient receptor potential (TRP) ion channels, which amplify neurogenic inflammation and pain. Protease-activated receptor 2 (PAR(2)), a receptor for inflammatory proteases, is a major mediator of neurogenic inflammation and pain. We investigated the signaling mechanisms by which PAR(2) regulates TRPV4 and determined the importance of tyrosine phosphorylation in this process. Human TRPV4 was expressed in HEK293 cells under control of a tetracycline-inducible promoter, allowing controlled and graded channel expression. In cells lacking TRPV4, the PAR(2) agonist stimulated a transient increase in [Ca(2+)](i). TRPV4 expression led to a markedly sustained increase in [Ca(2+)](i). Removal of extracellular Ca(2+) and treatment with the TRPV4 antagonists Ruthenium Red or HC067047 prevented the sustained response. Inhibitors of phospholipase A(2) and cytochrome P450 epoxygenase attenuated the sustained response, suggesting that PAR(2) generates arachidonic acid-derived lipid mediators, such as 5',6'-EET, that activate TRPV4. Src inhibitor 1 suppressed PAR(2)-induced activation of TRPV4, indicating the importance of tyrosine phosphorylation. The TRPV4 tyrosine mutants Y110F, Y805F, and Y110F/Y805F were expressed normally at the cell surface. However, PAR(2) was unable to activate TRPV4 with the Y110F mutation. TRPV4 antagonism suppressed PAR(2) signaling to primary nociceptive neurons, and TRPV4 deletion attenuated PAR(2)-stimulated neurogenic inflammation. Thus, PAR(2) activation generates a signal that induces sustained activation of TRPV4, which requires a key tyrosine residue (TRPV4-Tyr-110). This mechanism partly mediates the proinflammatory actions of PAR(2).
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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.