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.
Highlights
Endocannabinoids can affect pancreatic  cell physiology
Endocannabinoid signaling has been implicated in modulating insulin release from  cells of the endocrine pancreas.  Cells express CB1 cannabinoid receptors (CB1Rs), and the enzymatic machinery regulating anandamide and 2-arachidonoylglycerol bioavailability
By combining molecular pharmacology and genetic tools in INS-1E cells and in vivo, we show that CB1R activation by endocannabinoids or synthetic agonists acutely or after prolonged exposure induces insulin hypersecretion
Summary
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. The presence of a functional endocannabinoid (eCB) system (that is, the enzymatic machinery to biosynthesize and degrade 2-arachidonoylglycerol (2-AG) and anandamide (AEA), as well as cannabinoid receptors) was identified in the endocrine pancreas [3,4,5,6] This endocannabinoid system is suggested to regulate insulin secretion [7, 8]. Instead of merely disrupting or degrading the pre-existing F-actin barrier [23], actin polymerization in stress fibers is stabilized at focal adhesion (FA) plaques containing e.g. paxilin, talin, and vinculin and serving to route insulin granules toward the plasma membrane [24] This mechanism rests on focal adhesion kinase (FAK) whose activity regulates FA remodeling and turnover [25, 26], and tension signaling [27], facilitating glucose-stimulated insulin secretion [28]. Our data suggest that eCBs coordinately activate ERK1/2/Akt and FAK downstream from CB1R to render the cytoskeleton permissive for insulin secretion
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