Mechanisms of protease‐activated receptor 2‐evoked hyperexcitability of nociceptive neurons innervating the mouse colon
Open accessAbstract
Agonists of protease‐activated receptor 2 (PAR 2) evoke hyperexcitability of dorsal root ganglia (DRG) neurons by unknown mechanisms. We examined the cellular mechanisms underlying PAR 2‐evoked hyperexcitability of mouse colonic DRG neurons to determine their potential role in pain syndromes such as visceral hyperalgesia. Colonic DRG neurons were identified by injecting Fast Blue and DiI retrograde tracers into the mouse colon. Using immunofluorescence, we found that DiI‐labelled neurons contained PAR 2 immunoreactivity, confirming the presence of receptors on colonic neurons. Whole‐cell current‐clamp recordings of acutely dissociated neurons demonstrated that PAR 2 activation with a brief application (3 min) of PAR 2 agonists, SLIGRL‐NH 2 and trypsin, evoked sustained depolarizations (up to 60 min) which were associated with increased input resistance and a marked reduction in rheobase (50% at 30 min). In voltage clamp, SLIGRL‐NH 2 markedly suppressed delayed rectifier IK currents (55% at 10 min), but had no effect on the transient IA current or TTX‐resistant Na+ currents. In whole‐cell current‐clamp recordings, the sustained excitability evoked by PAR 2 activation was blocked by the PKC inhibitor, calphostin, and the ERK 1/2 inhibitor PD98059. Studies of ERK 1/2 phosphorylation using confocal microscopy demonstrated that SLIGRL‐NH 2 increased levels of immunoreactive pERK 1/2 in DRG neurons, particularly in proximity to the plasma membrane. Thus, activation of PAR 2 receptors on colonic nociceptive neurons causes sustained hyperexcitability that is related, at least in part, to suppression of delayed rectifier IK currents. Both PKC and ERK 1/2 mediate the PAR 2‐induced hyperexcitability. These studies describe a novel mechanism of sensitization of colonic nociceptive neurons that may be implicated in conditions of visceral hyperalgesia such as irritable bowel syndrome.
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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 [153]
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- Authors
- Kayssi, A., Amadesi, S., Bautista, F., Bunnett, N. W., & Vanner, S.
- Affiliations
- Queen's University (CA)
- University of California, San Francisco (US)
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2007-04-16
- Volume
- 580
- Issue
- 3
- Pages
- 977-991
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC2075455
- OpenAlex
- W1499400472
- Semantic Scholar
- 36a57debf2943d43d9712cb3dd358d449c51bfd4
- Cited by
- 64
- References
- 47
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 3 · 2018: 1 · 2017: 3 · 2016: 5 · 2015: 4 · 2013: 1 · 2012: 4
- FWCI
- 5.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CentAUR (University of Reading) (submittedVersion)
- Funders
- Crohn's and Colitis Foundation of Canada
- National Institutes of Health
- U.S. Public Health Service (D43207)
- Canadian Institutes of Health Research (DK57840)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 57840, R01DK057840)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- protease-activated receptor 2, nociceptors, dorsal root ganglia, visceral hypersensitivity, colonic pain, neuronal hyperexcitability, delayed rectifier potassium current, ERK signaling, protein kinase C, SLIGRL-NH2, trypsin, irritable bowel syndrome, sensory neuron sensitization
- MeSH terms
- Animals, Cell Membrane, Cells, Cultured, Colon, Drug Resistance, Electric Conductivity, Enzyme Activation, Female, Ganglia, Spinal, Male, Mice, Inbred Strains, Neurons, Nociceptors, Oligopeptides, Phosphorylation, Protein Kinase C, Tetrodotoxin, Trypsin, Potassium Channels, Sodium Channels, Patch-Clamp Techniques, Receptor, PAR-2, Extracellular Signal-Regulated MAP Kinases, Mice
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