Adenosine triphosphate is co-secreted with glucagon-like peptide-1 to modulate intestinal enterocytes and afferent neurons

Van B Lu,Andrew B Leiter,Fiona M Gribble,Juraj Rievaj,Luke A Pattison,Christopher A Smith,Elisabeth A O’Flaherty,Gwen Tolhurst,Ramona Pais,David C Bulmer,Frank Reimann

doi:10.1038/s41467-019-09045-9

Van B Lu, Andrew B Leiter + Show 9 more

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https://doi.org/10.1038/s41467-019-09045-9

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Enteroendocrine cells are specialised sensory cells located in the intestinal epithelium and generate signals in response to food ingestion. Whilst traditionally considered hormone-producing cells, there is evidence that they also initiate activity in the afferent vagus nerve and thereby signal directly to the brainstem. We investigate whether enteroendocrine L-cells, well known for their production of the incretin hormone glucagon-like peptide-1 (GLP-1), also release other neuro-transmitters/modulators. We demonstrate regulated ATP release by ATP measurements in cell supernatants and by using sniffer patches that generate electrical currents upon ATP exposure. Employing purinergic receptor antagonists, we demonstrate that evoked ATP release from L-cells triggers electrical responses in neighbouring enterocytes through P2Y2 and nodose ganglion neurones in co-cultures through P2X2/3-receptors. We conclude that L-cells co-secrete ATP together with GLP-1 and PYY, and that ATP acts as an additional signal triggering vagal activation and potentially synergising with the actions of locally elevated peptide hormone concentrations.

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Enteroendocrine cells are specialised sensory cells located in the intestinal epithelium and generate signals in response to food ingestion
In response to various stimuli following food ingestion, they release a host of gut peptide hormones, including glucagon-like peptide 1 (GLP-1), which is secreted from a subpopulation of EECs traditionally called L-cells, that at least in the distal intestine often co-secrete peptide YY (PYY)[1]
We showed previously that glucagon-like peptide-1 (GLP-1) application in isolation did little to cytosolic Ca2+-concentrations in Glp1r-expressing neurons isolated from nodose ganglia, consistent with the known predominant Gs-coupling of GLP1R; co-application of GLP-1 with adenosine triphosphate (ATP), a strong activator of these neurons, resulted in significantly stronger Ca2+-signals than ATP application alone[3]

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Enteroendocrine cells are specialised sensory cells located in the intestinal epithelium and generate signals in response to food ingestion. ATP concentrations in GLUTag cell culture supernatants were significantly elevated following cell stimulation with a mixture of forskolin, IBMX and high glucose (Fig. 2a) and similar results were obtained in the absence of ectonucleotidase inhibition (Supplementary Figure 1b).

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