The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice.
Level 5 - mechanism / opinion, no new human data
Preclinical in vitro and animal model
PubMed 25194674 · doi:10.1053/j.gastro.2014.08.042
What was done
Researchers investigated the role of the ion channel TRPA1 in bile acid (BA)-evoked, TGR5-dependent itch. Co-expression of TGR5 and TRPA1 in mouse cutaneous afferents was assessed using immunofluorescence, in situ hybridization, and single-cell PCR. Intracellular Ca2+ signaling downstream of TGR5 was examined in HEK293 cells, Xenopus oocytes, and primary sensory neurons. The effects of TRPA1 pharmacological antagonism or genetic disruption (Trpa1-/-) on spinal neuropeptide release, spinal Fos expression, and scratching behaviors were evaluated in wild-type and TGR5-overexpressing mice.
What was found
The abstract reports qualitative mechanistic findings without numeric values or statistical metrics. TGR5 and TRPA1 were co-expressed in cutaneous afferent neurons. In vitro, bile acids stimulated TGR5-dependent TRPA1 activation and sensitization via Gβγ, protein kinase C, and Ca2+. In vivo, TRPA1 deletion or antagonism prevented BA-induced release of gastrin-releasing peptide and atrial natriuretic peptide B, blocked spinal neuronal Fos expression, and prevented BA-induced scratching. In TGR5-overexpressing mice with elevated spontaneous scratching, a TRPA1 antagonist or the bile acid sequestrant colestipol suppressed the scratching response.
Why it matters
The findings identify a functional signaling link between the bile acid receptor TGR5 and the ion channel TRPA1 in sensory neurons, suggesting potential therapeutic targets for cholestatic pruritus.
Limits
The study is restricted to cell lines and mouse models, with no direct testing in human subjects. The abstract does not provide sample sizes, animal counts, numerical effect sizes, or confidence intervals.
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