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A Targeted RNAi Screen Identifies Endocytic Trafficking Factors That Control GLP-1 Receptor Signaling in Pancreatic β-Cells.
- Source :
-
Diabetes . Mar2018, Vol. 67 Issue 3, p385-399. 15p. - Publication Year :
- 2018
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *PROTEIN metabolism
*ANIMAL experimentation
*CELL lines
*CELLULAR signal transduction
*COMPARATIVE studies
*CYCLIC adenylic acid
*ELECTRON microscopy
*ENDOCYTOSIS
*GENES
*INSULIN
*ISLANDS of Langerhans
*LYSOSOMES
*RESEARCH methodology
*INCRETINS
*MEDICAL cooperation
*MICE
*PEPTIDES
*PROTEINS
*RECOMBINANT proteins
*RESEARCH
*RESEARCH funding
*TISSUE culture
*VENOM
*DNA-binding proteins
*EVALUATION research
*CHEMICAL inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 00121797
- Volume :
- 67
- Issue :
- 3
- Database :
- Academic Search Index
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 128134113
- Full Text :
- https://doi.org/10.2337/db17-0639