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The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice.
Gastroenterology. 2014 Dec; 147(6):1417-28.G

Abstract

BACKGROUND & AIMS

Patients with cholestatic disease have increased systemic concentrations of bile acids (BAs) and profound pruritus. The G-protein-coupled BA receptor 1 TGR5 (encoded by GPBAR1) is expressed by primary sensory neurons; its activation induces neuronal hyperexcitability and scratching by unknown mechanisms. We investigated whether the transient receptor potential ankyrin 1 (TRPA1) is involved in BA-evoked, TGR5-dependent pruritus in mice.

METHODS

Co-expression of TGR5 and TRPA1 in cutaneous afferent neurons isolated from mice was analyzed by immunofluorescence, in situ hybridization, and single-cell polymerase chain reaction. TGR5-induced activation of TRPA1 was studied in in HEK293 cells, Xenopus laevis oocytes, and primary sensory neurons by measuring Ca(2+) signals. The contribution of TRPA1 to TGR5-induced release of pruritogenic neuropeptides, activation of spinal neurons, and scratching behavior were studied using TRPA1 antagonists or Trpa1(-/-) mice.

RESULTS

TGR5 and TRPA1 protein and messenger RNA were expressed by cutaneous afferent neurons. In HEK cells, oocytes, and neurons co-expressing TGR5 and TRPA1, BAs caused TGR5-dependent activation and sensitization of TRPA1 by mechanisms that required Gβγ, protein kinase C, and Ca(2+). Antagonists or deletion of TRPA1 prevented BA-stimulated release of the pruritogenic neuropeptides gastrin-releasing peptide and atrial natriuretic peptide B in the spinal cord. Disruption of Trpa1 in mice blocked BA-induced expression of Fos in spinal neurons and prevented BA-stimulated scratching. Spontaneous scratching was exacerbated in transgenic mice that overexpressed TRG5. Administration of a TRPA1 antagonist or the BA sequestrant colestipol, which lowered circulating levels of BAs, prevented exacerbated spontaneous scratching in TGR5 overexpressing mice.

CONCLUSIONS

BAs induce pruritus in mice by co-activation of TGR5 and TRPA1. Antagonists of TGR5 and TRPA1, or inhibitors of the signaling mechanism by which TGR5 activates TRPA1, might be developed for treatment of cholestatic pruritus.

Authors+Show Affiliations

Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia; Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia.Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.Health Innovations Research Institute and School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia.Health Innovations Research Institute and School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia.Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia.Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia.Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.Charles Institute for Translational Dermatology, University College Dublin, Dublin, Ireland.Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy.Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy.Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy.Department of Surgery, University of California, San Francisco, San Francisco, California.Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia; Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia. Electronic address: Nigel.Bunnett@Monash.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25194674

Citation

Lieu, TinaMarie, et al. "The Bile Acid Receptor TGR5 Activates the TRPA1 Channel to Induce Itch in Mice." Gastroenterology, vol. 147, no. 6, 2014, pp. 1417-28.
Lieu T, Jayaweera G, Zhao P, et al. The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology. 2014;147(6):1417-28.
Lieu, T., Jayaweera, G., Zhao, P., Poole, D. P., Jensen, D., Grace, M., McIntyre, P., Bron, R., Wilson, Y. M., Krappitz, M., Haerteis, S., Korbmacher, C., Steinhoff, M. S., Nassini, R., Materazzi, S., Geppetti, P., Corvera, C. U., & Bunnett, N. W. (2014). The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology, 147(6), 1417-28. https://doi.org/10.1053/j.gastro.2014.08.042
Lieu T, et al. The Bile Acid Receptor TGR5 Activates the TRPA1 Channel to Induce Itch in Mice. Gastroenterology. 2014;147(6):1417-28. PubMed PMID: 25194674.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. AU - Lieu,TinaMarie, AU - Jayaweera,Gihan, AU - Zhao,Peishen, AU - Poole,Daniel P, AU - Jensen,Dane, AU - Grace,Megan, AU - McIntyre,Peter, AU - Bron,Romke, AU - Wilson,Yvette M, AU - Krappitz,Matteus, AU - Haerteis,Silke, AU - Korbmacher,Christoph, AU - Steinhoff,Martin S, AU - Nassini,Romina, AU - Materazzi,Serena, AU - Geppetti,Pierangelo, AU - Corvera,Carlos U, AU - Bunnett,Nigel W, Y1 - 2014/09/03/ PY - 2014/04/24/received PY - 2014/08/19/revised PY - 2014/08/26/accepted PY - 2014/9/8/entrez PY - 2014/9/10/pubmed PY - 2015/2/5/medline KW - Itching KW - Liver KW - Mouse Model KW - Signal Transduction SP - 1417 EP - 28 JF - Gastroenterology JO - Gastroenterology VL - 147 IS - 6 N2 - BACKGROUND & AIMS: Patients with cholestatic disease have increased systemic concentrations of bile acids (BAs) and profound pruritus. The G-protein-coupled BA receptor 1 TGR5 (encoded by GPBAR1) is expressed by primary sensory neurons; its activation induces neuronal hyperexcitability and scratching by unknown mechanisms. We investigated whether the transient receptor potential ankyrin 1 (TRPA1) is involved in BA-evoked, TGR5-dependent pruritus in mice. METHODS: Co-expression of TGR5 and TRPA1 in cutaneous afferent neurons isolated from mice was analyzed by immunofluorescence, in situ hybridization, and single-cell polymerase chain reaction. TGR5-induced activation of TRPA1 was studied in in HEK293 cells, Xenopus laevis oocytes, and primary sensory neurons by measuring Ca(2+) signals. The contribution of TRPA1 to TGR5-induced release of pruritogenic neuropeptides, activation of spinal neurons, and scratching behavior were studied using TRPA1 antagonists or Trpa1(-/-) mice. RESULTS: TGR5 and TRPA1 protein and messenger RNA were expressed by cutaneous afferent neurons. In HEK cells, oocytes, and neurons co-expressing TGR5 and TRPA1, BAs caused TGR5-dependent activation and sensitization of TRPA1 by mechanisms that required Gβγ, protein kinase C, and Ca(2+). Antagonists or deletion of TRPA1 prevented BA-stimulated release of the pruritogenic neuropeptides gastrin-releasing peptide and atrial natriuretic peptide B in the spinal cord. Disruption of Trpa1 in mice blocked BA-induced expression of Fos in spinal neurons and prevented BA-stimulated scratching. Spontaneous scratching was exacerbated in transgenic mice that overexpressed TRG5. Administration of a TRPA1 antagonist or the BA sequestrant colestipol, which lowered circulating levels of BAs, prevented exacerbated spontaneous scratching in TGR5 overexpressing mice. CONCLUSIONS: BAs induce pruritus in mice by co-activation of TGR5 and TRPA1. Antagonists of TGR5 and TRPA1, or inhibitors of the signaling mechanism by which TGR5 activates TRPA1, might be developed for treatment of cholestatic pruritus. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/25194674/The_bile_acid_receptor_TGR5_activates_the_TRPA1_channel_to_induce_itch_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(14)01081-6 DB - PRIME DP - Unbound Medicine ER -