Academic Journal
Free fatty acid receptor 1 stimulates cAMP production and gut hormone secretion through Gq-mediated activation of adenylate cyclase 2
| العنوان: | Free fatty acid receptor 1 stimulates cAMP production and gut hormone secretion through Gq-mediated activation of adenylate cyclase 2 |
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| المؤلفون: | Jacob Emil Petersen, Maria Hauge Pedersen, Oksana Dmytriyeva, Emilie Nellemose, Tulika Arora, Maja Storm Engelstoft, Wesley B. Asher, Jonathan A. Javitch, Thue W. Schwartz, Mette Trauelsen |
| المصدر: | Molecular Metabolism, Vol 74, Iss , Pp 101757- (2023) |
| بيانات النشر: | Elsevier |
| سنة النشر: | 2023 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | FFAR1, GPR40, Adenylate cyclase 2, GLP-1, ADCY2, Gq, Internal medicine, RC31-1245 |
| الوصف: | Objective: Free fatty acid receptor 1 (FFAR1) is highly expressed in enteroendocrine cells of the small intestine and pancreatic beta cells, where FFAR1 agonists function as GLP-1 and insulin secretagogues, respectively. Most efficacious are so-called second-generation synthetic agonists such as AM5262, which, in contrast to endogenous long-chain fatty acids are able to signal through both IP3/Ca2+ and cAMP pathways. Whereas IP3 signaling is to be expected for the mainly Gq-coupled FFAR1, the mechanism behind FFAR1-induced cAMP accumulation remains unclear, although originally proposed to be Gs mediated. Methods and results: When stimulated with AM5262, we observe that FFAR1 can activate the majority of the Gα proteins, except - surprisingly - members of the Gs family. AM5262-induced FFAR1-mediated transcriptional activation through cAMP response element (CREB) was blocked by the specific Gq inhibitor, YM253890. Furthermore, in Gq-deficient cells no CREB signal was observed unless Gq or G11 was reintroduced by transfection. By qPCR we determined that adenylate cyclase 2 (Adcy2) was highly expressed and enriched relative to the nine other Adcys in pro-glucagon expressing enteroendocrine cells. Co-transfection with ADCY2 increased the FFAR1-induced cAMP response 4-5-fold in WT HEK293 cells, an effect fully inhibited by YM253890. Moreover, co-transfection with ADCY2 had no effect in Gq-deficient cells without reintroduction of either Gq or G11. Importantly, although both AM5262/FFAR1 and isoproterenol/β2 adrenergic receptor (β2AR) induced cAMP production was lost in Gs-deficient cells, only the β2AR response was rescued by Gs transfection, whereas co-transfection with ADCY2 was required to rescue the FFAR1 cAMP response. In situ hybridization demonstrated a high degree of co-expression of ADCY2 and FFAR1 in enteroendocrine cells throughout the intestine. Finally, in the enteroendocrine STC-1 and GLUTag cell lines AM5262-induced cAMP accumulation and GLP-1 secretion were both blocked by YM253890. Conclusions: Our ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2212-8778 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S2212877823000911; https://doaj.org/toc/2212-8778; https://doaj.org/article/a28f704e33e846e698b98299456a1403 |
| DOI: | 10.1016/j.molmet.2023.101757 |
| الاتاحة: | https://doi.org/10.1016/j.molmet.2023.101757 https://doaj.org/article/a28f704e33e846e698b98299456a1403 |
| رقم الانضمام: | edsbas.313FFF71 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 22128778 |
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| DOI: | 10.1016/j.molmet.2023.101757 |