CB1 Cannabinoid Receptors Couple to Focal Adhesion Kinase to Control Insulin Release

Background: Endocannabinoids can affect pancreatic cell physiology. Results: Anandamide and 2-arachidonoylglycerol binding to CB1 receptors induces focal adhesion kinase phosphorylation, which is a prerequisite of insulin release. Conclusion: Focal adhesion kinase activation downstream from CB1 receptors couples cytoskeletal reorganization to insulin release. Significance: Identifies the molecular blueprint of 2-arachidonoylglycerol signaling in the endocrine pancreas, and outlines a kinase activation cascade linking endocannabinoid signals to insulin release. Endocannabinoid signaling has been implicated in modulating insulin release from cells of the endocrine pancreas. Cells express CB1 cannabinoid receptors (CB(1)Rs), 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, CB(1)Rs 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 CB(1)Rs 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.