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CB1 Cannabinoid Receptors Couple to Focal Adhesion Kinase to Control Insulin Release
Authors:Katarzyna Malenczyk  Magdalena Jazurek  Erik Keimpema  Cristoforo Silvestri  Justyna Janikiewicz  Ken Mackie  Vincenzo Di Marzo  Maria J. Redowicz  Tibor Harkany  Agnieszka Dobrzyn
Abstract:Endocannabinoid signaling has been implicated in modulating insulin release from β cells of the endocrine pancreas. β Cells express CB1 cannabinoid receptors (CB1Rs), and the enzymatic machinery regulating anandamide and 2-arachidonoylglycerol bioavailability. However, the molecular cascade coupling agonist-induced cannabinoid receptor activation to insulin release remains unknown. By combining molecular pharmacology and genetic tools in INS-1E cells and in vivo, we show that CB1R activation by endocannabinoids (anandamide and 2-arachidonoylglycerol) or synthetic agonists acutely or after prolonged exposure induces insulin hypersecretion. In doing so, CB1Rs recruit Akt/PKB and extracellular signal-regulated kinases 1/2 to phosphorylate focal adhesion kinase (FAK). FAK activation induces the formation of focal adhesion plaques, multimolecular platforms for second-phase insulin release. Inhibition of endocannabinoid synthesis or FAK activity precluded insulin release. We conclude that FAK downstream from CB1Rs mediates endocannabinoid-induced insulin release by allowing cytoskeletal reorganization that is required for the exocytosis of secretory vesicles. These findings suggest a mechanistic link between increased circulating and tissue endocannabinoid levels and hyperinsulinemia in type 2 diabetes.
Keywords:Cannabinoid Receptors   Cytoskeleton   Endocannabinoids   Exocytosis   Focal Adhesion Kinase   Insulin Release
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