Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome
Open accessAbstract
Significance: Activated G protein-coupled receptors (GPCRs) internalize and can continue to signal from endosomes. The contribution of endosomal signaling to human disease is unknown. Proteases that are generated in the colon of patients with irritable bowel syndrome (IBS) can cleave protease-activated receptor-2 (PAR 2 ) on nociceptors to cause pain. We evaluated whether PAR 2 generates signals in endosomes of nociceptors that mediate persistent hyperexcitability and pain. Biopsies of colonic mucosa from IBS patients released proteases that induced PAR 2 endocytosis, endosomal signaling, and persistent hyperexcitability of nociceptors. When conjugated to the transmembrane lipid cholestanol, PAR 2 antagonists accumulated in endosomes and suppressed persistent hyperexcitability. The results reveal the therapeutic potential of endosomally targeted PAR 2 antagonists for IBS pain, and expand the contribution of endosomal GPCR signaling to encompass processes that are relevant to disease.
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PARs have been implicated in the pathogenesis of colorectal cancer and inflammatory and functional intestinal disorders.
“PARs have been implicated in the pathogenesis of colorectal cancer138 and inflammatory and functional intestinal disorders.139–141”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [141]
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- Authors
- Jimenez-Vargas, N. N., Pattison, L. A., Zhao, P., Lieu, T., Latorre, R., Jensen, D. D., Castro, J., Aurelio, L., Le, G. T., Flynn, B., Herenbrink, C. K., Yeatman, H. R., Edgington-Mitchell, L., Porter, C. J. H., Halls, M. L., Canals, M., Veldhuis, N. A., Poole, D. P., McLean, P., Hicks, G. A., Scheff, N., Chen, E., Bhattacharya, A., Schmidt, B. L., Brierley, S. M., Vanner, S. J., & Bunnett, N. W.
- Affiliations
- Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queen’s University, Kingston, ON K7L 2V7, Canada;
- Australian Research Council (AU)
- Columbia University (US)
- Flinders University (AU)
- Monash Institute of Pharmaceutical Sciences and Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, VIC 3052, Australia;
- Takeda (United States) (US)
- New York University (US)
- Queen's University (CA)
- ORCID
- Pattison, Luke A.
- Zhao, Peishen
- Lieu, TinaMarie
- Latorre, Rocco
- Jensen, Dane D.
- Castro, Joel
- Flynn, Bernard
- Herenbrink, Carmen Klein
- Yeatman, Holly R.
- Porter, Christopher J. H.
- Halls, Michelle L.
- Canals, Meritxell
- Veldhuis, Nicholas A.
- Poole, Daniel P.
- McLean, Peter
- Hicks, Gareth A.
- Scheff, Nicole
- Bhattacharya, Aditi
- Schmidt, Brian L.
- Brierley, Stuart M.
- Vanner, Stephen J.
- Bunnett, Nigel W.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-07-16
- Volume
- 115
- Issue
- 31
- Pages
- E7438-E7447
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6077730
- OpenAlex
- W2883889243
- Cited by
- 185
- References
- 46
- Citations by year
- 2026: 16 · 2025: 14 · 2024: 23 · 2023: 28 · 2022: 25 · 2021: 25 · 2020: 25 · 2019: 22 · 2018: 6
- FWCI
- 19.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Monash University Research Portal (Monash University) (submittedVersion, other-oa)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Repository@Nottingham (University of Nottingham) (submittedVersion)
- Funders
- HHS | NIH | National Institute of Neurological Disorders and Stroke (NS102722)
- HHS | NIH | National Institute of Dental and Craniofacial Research (DE026806)
- Department of Health | National Health and Medical Research Council (63303, 1061687, 1126378)
- Australian Research Council (CE140100036)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- protease-activated receptor 2, endosomal signaling, irritable bowel syndrome, visceral pain, nociceptors, G protein-coupled receptor internalization, endocytosis, PAR2 antagonists, cholestanol
- MeSH terms
- Animals, Endocytosis, Humans, Nociceptors, Endosomes, Trypsin, Signal Transduction, Irritable Bowel Syndrome, Receptor, PAR-2, Extracellular Signal-Regulated MAP Kinases, Nociception, Chronic Pain
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