| First Author | Malenczyk K | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 45 | Pages | 32685-99 |
| PubMed ID | 24089517 | Mgi Jnum | J:204989 |
| Mgi Id | MGI:5543848 | Doi | 10.1074/jbc.M113.478354 |
| Citation | Malenczyk K, et al. (2013) CB1 cannabinoid receptors couple to focal adhesion kinase to control insulin release. J Biol Chem 288(45):32685-99 |
| abstractText | Endocannabinoid signaling has been implicated in modulating insulin release from beta cells of the endocrine pancreas. beta 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. |
