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.
© 2017 by the American Diabetes Association.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcium Signaling / drug effects
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Cell Line
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Cyclic AMP / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Endocytosis* / drug effects
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Exenatide
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Glucagon-Like Peptide-1 Receptor / genetics
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Glucagon-Like Peptide-1 Receptor / metabolism
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Glucagon-Like Peptide-1 Receptor Agonists*
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Humans
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Incretins / pharmacology
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Insulin / metabolism
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Insulin Secretion
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Insulin-Secreting Cells / drug effects
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Insulin-Secreting Cells / metabolism*
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Insulin-Secreting Cells / ultrastructure
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Lysosomes / drug effects
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Lysosomes / enzymology
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Lysosomes / metabolism
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Lysosomes / ultrastructure
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Mice
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Microscopy, Electron, Transmission
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Peptides / pharmacology
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RNA Interference
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Second Messenger Systems* / drug effects
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Sorting Nexins / antagonists & inhibitors
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Sorting Nexins / genetics
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Sorting Nexins / metabolism*
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Tissue Culture Techniques
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Venoms / pharmacology
Substances
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DNA-Binding Proteins
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GLP1R protein, human
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Glp1r protein, mouse
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Glucagon-Like Peptide-1 Receptor
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HIP1 protein, human
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Hip1 protein, mouse
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Incretins
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Insulin
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Peptides
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Recombinant Fusion Proteins
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SNX1 protein, human
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SNX1 protein, mouse
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SNX27 protein, human
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Snx27 protein, mouse
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Sorting Nexins
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Venoms
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Exenatide
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Cyclic AMP
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Glucagon-Like Peptide-1 Receptor Agonists