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A Targeted RNAi Screen Identifies Endocytic Trafficking Factors That Control GLP-1 Receptor Signaling in Pancreatic β-Cells

Buenaventura, Teresa
Kanda, Nisha
Douzenis, Phoebe C
Jones, Ben
Bloom, Stephen R
Chabosseau, Pauline
Corrêa, Ivan R (Jr)
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Published in Diabetes. 2018, vol. 67, no. 3, p. 385-399
Abstract The glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) is a key target for type 2 diabetes (T2D) treatment. Because endocytic trafficking of agonist-bound receptors is one of the most important routes for regulation of receptor signaling, a better understanding of this process may facilitate the development of new T2D therapeutic strategies. Here, we screened 29 proteins with known functions in G protein-coupled receptor trafficking for their role in GLP-1R potentiation of insulin secretion in pancreatic β-cells. We identify five (clathrin, dynamin1, AP2, sorting nexins [SNX] SNX27, and SNX1) that increase and four (huntingtin-interacting protein 1 [HIP1], HIP14, GASP-1, and Nedd4) that decrease insulin secretion from murine insulinoma MIN6B1 cells in response to the GLP-1 analog exendin-4. The roles of HIP1 and the endosomal SNX1 and SNX27 were further characterized in mouse and human β-cell lines and human islets. While HIP1 was required for the coupling of cell surface GLP-1R activation with clathrin-dependent endocytosis, the SNXs were found to control the balance between GLP-1R plasma membrane recycling and lysosomal degradation and, in doing so, determine the overall β-cell incretin responses. We thus identify key modulators of GLP-1R trafficking and signaling that might provide novel targets to enhance insulin secretion in T2D.
Keywords AnimalsCalcium Signaling/drug effectsCell LineCyclic AMP/metabolismDNA-Binding Proteins/antagonists & inhibitors/genetics/metabolismEndocytosis/drug effectsExenatideGlucagon-Like Peptide-1 Receptor/agonists/genetics/metabolismHumansIncretins/pharmacologyInsulin/metabolismInsulin SecretionInsulin-Secreting Cells/drug effects/metabolism/ultrastructureLysosomes/drug effects/enzymology/metabolism/ultrastructureMiceMicroscopyElectronTransmissionPeptides/pharmacologyRNA InterferenceRecombinant Fusion Proteins/chemistry/metabolismSecond Messenger Systems/drug effectsSorting Nexins/antagonists & inhibitors/genetics/metabolismTissue Culture TechniquesVenoms/pharmacology
PMID: 29284659
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Research group La transplantation d'îlots de Langerhans (623)
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BUENAVENTURA, Teresa et al. A Targeted RNAi Screen Identifies Endocytic Trafficking Factors That Control GLP-1 Receptor Signaling in Pancreatic β-Cells. In: Diabetes, 2018, vol. 67, n° 3, p. 385-399. doi: 10.2337/db17-0639 https://archive-ouverte.unige.ch/unige:116918

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Deposited on : 2019-05-03

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