Mast cell tryptase and proteinase‐activated receptor 2 induce hyperexcitability of guinea‐pig submucosal neurons
Open accessAbstract
Mast cells that are in close proximity to autonomic and enteric nerves release several mediators that cause neuronal hyperexcitability. This study examined whether mast cell tryptase evokes acute and long‐term hyperexcitability in submucosal neurons from the guinea‐pig ileum by activating proteinase‐activated receptor 2 (PAR2) on these neurons. We detected the expression of PAR2 in the submucosal plexus using RT‐PCR. Most submucosal neurons displayed PAR2 immunoreactivity, including those colocalizing VIP. Brief (minutes) application of selective PAR2 agonists, including trypsin, the activating peptide SL‐NH 2 and mast cell tryptase, evoked depolarizations of the submucosal neurons, as measured with intracellular recording techniques. The membrane potential returned to resting values following washout of agonists, but most neurons were hyperexcitable for the duration of recordings (> 30 min–hours) and exhibited an increased input resistance and amplitude of fast EPSPs. Trypsin, in the presence of soybean trypsin inhibitor, and the reverse sequence of the activating peptide (LR‐NH 2) had no effect on neuronal membrane potential or long‐term excitability. Degranulation of mast cells in the presence of antagonists of established excitatory mast cell mediators (histamine, 5‐HT, prostaglandins) also caused depolarization, and following washout of antigen, long‐term excitation was observed. Mast cell degranulation resulted in the release of proteases, which desensitized neurons to other agonists of PAR2. Our results suggest that proteases from degranulated mast cells cleave PAR2 on submucosal neurons to cause acute and long‐term hyperexcitability. This signalling pathway between immune cells and neurons is a previously unrecognized mechanism that could contribute to chronic alterations in visceral function.
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Agonists of PARs excite spinal afferent neurons that innervate the GI tract.
“Agonists of PARs excite spinal afferent neurons that innervate the GI tract.153,154”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [154]
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- Authors
- Reed, D. E., Barajas‐Lopez, C., Cottrell, G., Velazquez‐Rocha, S., Dery, O., Grady, E. F., Bunnett, N. W., & Vanner, S. J.
- Affiliations
- Queen's University (CA)
- University of California, San Francisco (US)
- Corresponding author
- Vanner, Stephen J.
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2003-03
- Volume
- 547
- Issue
- 2
- Pages
- 531-542
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC2342663
- OpenAlex
- W1983033537
- Cited by
- 192
- References
- 49
- Citations by year
- 2026: 10 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 8 · 2021: 6 · 2020: 7 · 2019: 6 · 2018: 8 · 2017: 7 · 2016: 5 · 2015: 4 · 2014: 7 · 2013: 5 · 2012: 13
- FWCI
- 4.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 57840, DK 43207, R01DK057840, R01DK043207, R56DK043207)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- tryptase, protease-activated receptor 2, neuronal hyperexcitability, submucosal neurons, enteric nervous system, mast cell degranulation, trypsin, VIP, visceral hypersensitivity, guinea pig ileum
- MeSH terms
- Animals, Electrophysiology, Guinea Pigs, Ileum, Immunohistochemistry, Lactoglobulins, Mast Cells, Neurons, Oligopeptides, Serine Endopeptidases, Submucous Plexus, Synapses, Tissue Distribution, Trypsin, Vasoactive Intestinal Peptide, Cell Degranulation, Receptors, Thrombin, Reverse Transcriptase Polymerase Chain Reaction, Receptor, PAR-2, Tryptases
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