TRPV4 stimulates colonic afferents through mucosal release of ATP and glutamate.

Autor: Meng MY; Department of Pharmacology, University of Cambridge, Cambridge, UK., Paine LW; Department of Pharmacology, University of Cambridge, Cambridge, UK., Sagnat D; IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France., Bello I; IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France.; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy., Oldroyd S; Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK., Javid F; Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, UK., Harper MT; Department of Pharmacology, University of Cambridge, Cambridge, UK., Hockley JRF; Department of Pharmacology, University of Cambridge, Cambridge, UK., St John Smith E; Department of Pharmacology, University of Cambridge, Cambridge, UK., Owens RM; Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK., Alric L; Internal Medicine Department of Digestive Disease, CHU Toulouse-Rangueil and Université de Toulouse, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France., Buscail E; IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France.; Department of Surgery, CHU Toulouse-Rangueil and Université de Toulouse, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France., Welsh F; BioPharmaceuticals R&D, AstraZeneca, Neuroscience, Cambridge, UK., Vergnolle N; IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Université Toulouse III-Paul Sabatier (UPS), Toulouse, France.; Department of Physiology and Pharmacology, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada., Bulmer DC; Department of Pharmacology, University of Cambridge, Cambridge, UK.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Dec 03. Date of Electronic Publication: 2024 Dec 03.
DOI: 10.1111/bph.17408
Abstrakt: 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 Ca 2+ 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 Ca 2+ 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.
(© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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