Journal
FRONTIERS IN PHYSIOLOGY
Volume 5, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphys.2014.00420
Keywords
cystathionine-gamma-lyase; GPCR signaling; oleanolic acid; enteroendocrine cells
Categories
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases Grants [DK28300, DK34153, 2T32 DK007150]
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Activation of plasma membrane TGR5 receptors in enteroendocrine cells by bile acids is known to regulate gastrointestinal secretion and motility and glucose homeostasis. The endocrine functions of the gut are modulated by microenvironment of the distal gut predominantly by sulfur-reducing bacteria of the microbiota that produce H2S. However, the mechanisms involved in the release of peptide hormones, GLP-1 and PYY in response to TGR5 activation by bile acids and the effect of H2S on bile acid-induced release of GLP-1 and PYY are unclear. In the present study, we have identified the signaling pathways activated by the bile acid receptor TGR5 to mediate GLP-1 and PYY release and the mechanism of inhibition of their release by H2S in enteroendocrine cells. The TGR5 ligand oleanolic acid (OA) stimulated Gas and cAMP formation, and caused GLP-1 and PYY release. OA-induced cAMP formation and peptide release were blocked by TGR5 siRNA. OA also caused an increase in PI hydrolysis and intracellular Ca2+. Increase in PI hydrolysis was abolished in cells transfected with PLC-epsilon siRNA. 8-pCPT-2'-O-Me-cAMP a selective activator of Epac, stimulated PI hydrolysis, and GLP-1 and PYY release. LCysteine, which activates endogenous H2S producing enzymes cystathionine-gamma-lyase and cystathionine-beta-synthase, and NaHS and GYY4137, which generate H2S, inhibited PI hydrolysis and GLP-1 and PYY release in response to OA or 8-pCPT-2'-O-Me-cAMP. Propargylglycine, an inhibitor of CSE, reversed the effect of Lcysteine on PI hydrolysis and GLP-1 and PYY release. We conclude: (i) activation of Gas-coupled TGR5 receptors causes stimulation of PI hydrolysis, and release of GLP-1 and PYY via a PKA-independent, cAMP-dependent mechanism involving Epac/PLC-epsilon/Ca2+ pathway, and (ii) H2S has potent inhibitory effects on GLP-1 and PYY release in response to TGR5 activation, and the mechanism involves inhibition of PLC-epsilon/Ca2+ pathway.
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