Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Mar;182(6):1324-1340.
doi: 10.1111/bph.17408. Epub 2024 Dec 3.

TRPV4 stimulates colonic afferents through mucosal release of ATP and glutamate

Michelle Y Meng  1 , Luke W Paine  1 , David Sagnat  2 , Ivana Bello  2   3 , Sophie Oldroyd  4 , Farideh Javid  5 , Matthew T Harper  1 , James R F Hockley  1 , Ewan St John Smith  1 , Róisín M Owens  4 , Laurent Alric  6 , Etienne Buscail  2   7 , Fraser Welsh  8 , Nathalie Vergnolle  2   9 , David C Bulmer  1
Affiliations

TRPV4 stimulates colonic afferents through mucosal release of ATP and glutamate

Michelle Y Meng et al. Br J Pharmacol. 2025 Mar.

Abstract

Background and purpose: Abdominal pain is a leading cause of morbidity for people living with gastrointestinal disease. Whereas the transient receptor potential vanilloid 4 (TRPV4) ion channel has been implicated in the pathogenesis of abdominal pain, the relative paucity of TRPV4 expression in colon-projecting sensory neurons suggests that non-neuronal cells may contribute to TRPV4-mediated nociceptor stimulation.

Experimental approach: Changes in murine colonic afferent activity were examined using ex vivo electrophysiology in tissues with the gut mucosa present or removed. ATP and glutamate release were measured by bioluminescence assays from human colon organoid cultures and mouse colon. Dorsal root ganglion sensory neuron activity was evaluated by Ca2+ imaging when cultured alone or co-cultured with colonic mucosa.

Key results: Bath application of TRPV4 agonist GSK1016790A elicited a robust increase in murine colonic afferent activity, which was abolished by removing the gut mucosa. GSK1016790A promoted ATP and glutamate release from human colon organoid cultures and mouse colon. Inhibition of ATP degradation in mouse colon enhanced the afferent response to GSK1016790A. Pretreatment with purinoceptor or glutamate receptor antagonists attenuated and abolished the response to GSK1016790A when given alone or in combination, respectively. Sensory neurons co-cultured with colonic mucosal cells produced a marked increase in intracellular Ca2+ to GSK1016790A compared with neurons cultured alone.

Conclusion and implications: Our data indicate that mucosal release of ATP and glutamate is responsible for the stimulation of colonic afferents following TRPV4 activation. These findings highlight an opportunity to target the gut mucosa for the development of new visceral analgesics.

Keywords: ATP; TRPV4; colonic afferents; glutamate; intestinal mucosa; visceral hypersensitivity.

PubMed Disclaimer

References

REFERENCES

    1. Aizawa, N., Wyndaele, J. J., Homma, Y., & Igawa, Y. (2012). Effects of TRPV4 cation channel activation on the primary bladder afferent activities of the rat. Neurourology and Urodynamics, 31(1), 148–155. https://doi.org/10.1002/NAU.21212
    1. Alessandri‐Haber, N., Yeh, J. J., Boyd, A. E., Parada, C. A., Chen, X., Reichling, D. B., & Levine, J. D. (2003). Hypotonicity induces TRPV4‐mediated nociception in rat. Neuron, 39(3), 497–511. https://doi.org/10.1016/S0896-6273(03)00462-8
    1. Alexander, S. P. H., Christopoulos, A., Davenport, A. P., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Southan, C., Davies, J. A., Abbracchio, M. P., Alexander, W., Al‐hosaini, K., Bäck, M., Barnes, N. M., Bathgate, R., … Ye, R. D. (2021). The Concise Guide to PHARMACOLOGY 2021/22: G protein‐coupled receptors. British Journal of Pharmacology, 178(S1), S27–S156. https://doi.org/10.1111/BPH.15538
    1. Alexander, S. P. H., Mathie, A., Peters, J. A., Veale, E. L., Striessnig, J., Kelly, E., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Southan, C., Davies, J. A., Aldrich, R. W., Attali, B., Baggetta, A. M., Becirovic, E., Biel, M., Bill, R. M., Catterall, W. A., … Zhu, M. (2021). The Concise Guide to PHARMACOLOGY 2021/22: Ion channels. British Journal of Pharmacology, 178(S1), S157–S245. https://doi.org/10.1111/BPH.15539/FULL
    1. Barbara, G., Stanghellini, V., De Giorgio, R., Cremon, C., Cottrell, G. S., Santini, D., Pasquinelli, G., Morselli‐Labate, A. M., Grady, E. F., Bunnett, N. W., Collins, S. M., & Corinaldesi, R. (2004). Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology, 126(3), 693–702. https://doi.org/10.1053/J.GASTRO.2003.11.055

MeSH terms

Substances

LinkOut - more resources