A critical role for β-catenin in modulating levels of insulin secretion from β-cells by regulating actin cytoskeleton and insulin vesicle localization
| Autor: | Waruni C. Dissanayake, Yanyun Fu, Kathryn Lee, Emmanuelle Cognard, Brie Sorrenson, Peter R. Shepherd, Weiping Han, William E. Hughes |
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| Přispěvatelé: | Sorrenson, Brie, Cognard, Emmanuelle, Lee, Kathryn L, Dissanayake, Waruni C, Fu, Yanyun, Han, Weiping, Hughes, William E, Shepherd, Peter R |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
endocrine system insulin actin cytoskeleton medicine.medical_treatment Incretin Biochemistry Exocytosis Cell Line 03 medical and health sciences Mice 0302 clinical medicine Glucagon-Like Peptide 1 Insulin-Secreting Cells Insulin Secretion medicine Animals Insulin Molecular Biology beta Catenin Chemistry Secretory Vesicles Wnt signaling pathway Actin remodeling Molecular Bases of Disease Cell Biology Actin cytoskeleton Secretory Vesicle Cell biology Actin Cytoskeleton 030104 developmental biology beta catenin Transcription Factor 7-Like 2 Protein 030217 neurology & neurosurgery Vesicle localization |
| Popis: | The processes regulating glucose-stimulated insulin secretion (GSIS) and its modulation by incretins in pancreatic β-cells are only partly understood. Here we investigate the involvement of β-catenin in these processes. Reducing β-catenin levels using siRNA knockdown attenuated GSIS in a range of β-cell models and blocked the ability of GLP-1 agonists and the depolarizing agent KCl to potentiate this. This could be mimicked in both β-cell models and isolated islets by short-term exposure to the β-catenin inhibitory drug pyrvinium. In addition, short-term treatment with a drug that increases β-catenin levels results in an increase in insulin secretion. The timing of these effects suggests that β-catenin is required for the processes regulating trafficking and/or release of pre-existing insulin granules rather than for those regulated by gene expression. This was supported by the finding that the overexpression of the transcriptional coactivator of β-catenin, transcription factor 7-like 2 (TCF7L2), attenuated insulin secretion, consistent with the extra TCF7L2 translocating β-catenin from the plasma membrane pool to the nucleus. We show that β-catenin depletion disrupts the intracellular actin cytoskeleton, and by using total internal reflectance fluorescence (TIRF) microscopy, we found that β-catenin is required for the glucose- and incretin-induced depletion of insulin vesicles from near the plasma membrane. In conclusion, we find that β-catenin levels modulate Ca2+-dependent insulin exocytosis under conditions of glucose, GLP-1, or KCl stimulation through a role in modulating insulin secretory vesicle localization and/or fusion via actin remodeling. These findings also provide insights as to how the overexpression of TCF7L2 may attenuate insulin secretion. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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