The Bile Acid Receptor TGR5 Activates the TRPA1 Channel to Induce Itch in Mice

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• 作者：TinaMarie Lieu¹ ; Gihan Jayaweera¹ ; Peishen Zhao¹ ; Daniel P. Poole¹ ; ² ; Dane Jensen¹ ; Megan Grace³ ; Peter McIntyre³ ; Romke Bron² ; Yvette M. Wilson² ; Matteus Krappitz⁴ ; Silke Haerteis⁴ ; Christoph Korbmacher⁴ ; Martin S. Steinhoff⁵ ; Romina Nassini⁶ ; Serena Materazzi⁶ ; Pierangelo Geppetti⁶ ; Carlos U. Corvera⁷ ; Nigel W. Bunnett¹ ; ⁸ ; ^{Nigel.Bunnett@Monash.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Liver ; Mouse Model ; Itching ; Signal Transduction
• 刊名：Gastroenterology
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：147
• 期：6
• 页码：1417-1428
• 全文大小：3776 K

文摘

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 Ca²⁺ 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 Ca²⁺. 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.