Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Gastroenterology
2014 Dec 01;1476:1417-28. doi: 10.1053/j.gastro.2014.08.042.
Show Gene links
Show Anatomy links
The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice.
Lieu T
,
Jayaweera G
,
Zhao P
,
Poole DP
,
Jensen D
,
Grace M
,
McIntyre P
,
Bron R
,
Wilson YM
,
Krappitz M
,
Haerteis S
,
Korbmacher C
,
Steinhoff MS
,
Nassini R
,
Materazzi S
,
Geppetti P
,
Corvera CU
,
Bunnett NW
.
???displayArticle.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.
Alemi,
The TGR5 receptor mediates bile acid-induced itch and analgesia.
2013, Pubmed
Alemi,
The TGR5 receptor mediates bile acid-induced itch and analgesia.
2013,
Pubmed
Amadesi,
Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice.
2006,
Pubmed
Angelin,
Postprandial serum bile acids in healthy man. Evidence for differences in absorptive pattern between individual bile acids.
1977,
Pubmed
Bautista,
TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents.
2006,
Pubmed
Bergasa,
The itch of liver disease.
2011,
Pubmed
Cho,
Identification of enteroendocrine cells that express TRPA1 channels in the mouse intestine.
2014,
Pubmed
Dascal,
Ion-channel regulation by G proteins.
2001,
Pubmed
European Association for the Study of the Liver,
EASL Clinical Practice Guidelines: management of cholestatic liver diseases.
2009,
Pubmed
Haerteis,
Plasmin and chymotrypsin have distinct preferences for channel activating cleavage sites in the γ subunit of the human epithelial sodium channel.
2012,
Pubmed
,
Xenbase
Ikoma,
The neurobiology of itch.
2006,
Pubmed
Imamachi,
TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms.
2009,
Pubmed
Jensen,
The bile acid receptor TGR5 does not interact with β-arrestins or traffic to endosomes but transmits sustained signals from plasma membrane rafts.
2013,
Pubmed
Jordt,
Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1.
2004,
Pubmed
Kawamata,
A G protein-coupled receptor responsive to bile acids.
2003,
Pubmed
Kirby,
Pruritic effect of bile salts.
1974,
Pubmed
Kremer,
Lysophosphatidic acid is a potential mediator of cholestatic pruritus.
2010,
Pubmed
Liu,
Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.
2009,
Pubmed
Magyar,
Plasma bile acid levels and liver disease.
1981,
Pubmed
Maruyama,
Identification of membrane-type receptor for bile acids (M-BAR).
2002,
Pubmed
Mela,
Review article: pruritus in cholestatic and other liver diseases.
2003,
Pubmed
Mishra,
The cells and circuitry for itch responses in mice.
2013,
Pubmed
Papacleovoulou,
Maternal cholestasis during pregnancy programs metabolic disease in offspring.
2013,
Pubmed
Poole,
Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous system.
2010,
Pubmed
Shimada,
Behavioral differentiation between itch and pain in mouse.
2008,
Pubmed
Steinhoff,
Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin.
2003,
Pubmed
Sun,
A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord.
2007,
Pubmed
Thomas,
TGR5-mediated bile acid sensing controls glucose homeostasis.
2009,
Pubmed
Wilson,
Visualization of functionally activated circuitry in the brain.
2002,
Pubmed
Wilson,
TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch.
2011,
Pubmed
Wilson,
The ion channel TRPA1 is required for chronic itch.
2013,
Pubmed
