Conley, Jason M.Jochim, AlexanderEvans-Molina, CarmellaWatts, Val J.Ren, Hongxia2025-02-182025-02-182024-12-25Conley JM, Jochim A, Evans-Molina C, Watts VJ, Ren H. G Protein-Coupled Receptor 17 Inhibits Glucagon-like Peptide-1 Secretion via a Gi/o-Dependent Mechanism in Enteroendocrine Cells. Biomolecules. 2024;15(1):9. Published 2024 Dec 25. doi:10.3390/biom15010009https://hdl.handle.net/1805/45775Gut peptides, including glucagon-like peptide-1 (GLP-1), regulate metabolic homeostasis and have emerged as the basis for multiple state-of-the-art diabetes and obesity therapies. We previously showed that G protein-coupled receptor 17 (GPR17) is expressed in intestinal enteroendocrine cells (EECs) and modulates nutrient-induced GLP-1 secretion. However, the GPR17-mediated molecular signaling pathways in EECs have yet to be fully deciphered. Here, we expressed the human GPR17 long isoform (hGPR17L) in GLUTag cells, a murine EEC line, and we used the GPR17 synthetic agonist MDL29,951 together with pharmacological probes and genetic approaches to quantitatively assess the contribution of GPR17 signaling to GLP-1 secretion. Constitutive hGPR17L activity inhibited GLP-1 secretion, and MDL29,951 treatment further inhibited this secretion, which was attenuated by treatment with the GPR17 antagonist HAMI3379. MDL29,951 promoted both Gi/o and Gq protein coupling to mediate cyclic AMP (cAMP) and calcium signaling. hGPR17L regulation of GLP-1 secretion appeared to be Gq-independent and dependent upon Gi/o signaling, but was not correlated with MDL29,951-induced whole-cell cAMP signaling. Our studies revealed key signaling mechanisms underlying the role of GPR17 in regulating GLP-1 secretion and suggest future opportunities for pharmacologically targeting GPR17 with inverse agonists to maximize GLP-1 secretion.en-USAttribution 4.0 InternationalG protein-coupled receptor (GPCR)Glucagon-like peptide 1 (GLP-1)Signal transductioncyclic AMP (cAMP)CalciumMetabolic diseaseDiabetesObesityArticle