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Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells
OBJECTIVES: The aim of this study was to investigate the electrical properties of ileal Glucagon-like peptide 1 (GLP-1) secreting L-cells using murine organoid cultures and the electrophysiological and intracellular signaling pathways recruited following activation of the G(αq)-coupled free fatty ac...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784317/ https://www.ncbi.nlm.nih.gov/pubmed/29167062 http://dx.doi.org/10.1016/j.molmet.2017.11.005 |
Sumario: | OBJECTIVES: The aim of this study was to investigate the electrical properties of ileal Glucagon-like peptide 1 (GLP-1) secreting L-cells using murine organoid cultures and the electrophysiological and intracellular signaling pathways recruited following activation of the G(αq)-coupled free fatty acid receptors FFA1 and G(αs)-coupled bile acid receptors GPBAR1. METHODS: Experiments were performed using ileal organoids generated from mice transgenically expressing fluorescent reporters (Epac2-camps and GCaMP3) under control of the proglucagon promoter. Electrophysiology and single cell imaging were performed on identified L-cells in organoids, and GLP-1 secretion from cultured organoids was measured by immunoassay. RESULTS: The FFA1 ligand TAK-875 triggered L-cell electrical activity, increased intracellular calcium, and activated a depolarizing current that was blocked by the TRPC3 inhibitor Pyr3. TAK-875 triggered GLP-1 secretion was Pyr3 sensitive, suggesting that the TRPC3 channel links FFA1 activation to calcium elevation and GLP-1 release in L-cells. GPBAR1 agonist triggered PKA-dependent L-type Ca(2+) current activation and action potential firing in L-cells. The combination of TAK-875 and a GPBAR1 agonist triggered synergistic calcium elevation and GLP-1 secretory responses. CONCLUSIONS: FFA1 and GPBAR1 activation individually increased electrical activity in L-cells by recruiting pathways that include activation of TRPC3 and L-type voltage-gated Ca(2+) channels. Synergy between the pathways activated downstream of these receptors was observed both at the level of Ca(2+) elevation and GLP-1 secretion. |
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