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Gastroenterology. 2014 Dec;147(6):1417-28. doi: 10.1053/j.gastro.2014.08.042. Epub 2014 Sep 3.

The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice.

Author information

1
Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.
2
Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia; Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia.
3
Health Innovations Research Institute and School of Medical Sciences, RMIT University, Bundoora, Victoria, Australia.
4
Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia.
5
Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
6
Charles Institute for Translational Dermatology, University College Dublin, Dublin, Ireland.
7
Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy.
8
Department of Surgery, University of California, San Francisco, San Francisco, California.
9
Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia; Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia. Electronic address: Nigel.Bunnett@Monash.edu.

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.

KEYWORDS:

Itching; Liver; Mouse Model; Signal Transduction

PMID:
25194674
PMCID:
PMC4821165
DOI:
10.1053/j.gastro.2014.08.042
[Indexed for MEDLINE]
Free PMC Article

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