CB1 cannabinoid receptors couple to focal adhesion kinase to control insulin release

Katarzyna Malenczyk, Magdalena Jazurek, Erik Keimpema, Cristoforo Silvestri, Justyna Janikiewicz, Ken Mackie, Vincenzo Di Marzo, Maria J. Redowicz, Tibor Harkany*, Agnieszka Dobrzyn

*Corresponding author for this work

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Endocannabinoid signaling has been implicated in modulating insulin release from β cells of the endocrine pancreas. β Cells express CB 1 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 CB 1R 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.

Original languageEnglish
Pages (from-to)32685-32699
Number of pages15
JournalJournal of Biological Chemistry
Volume288
Issue number45
Early online date2 Oct 2013
DOIs
Publication statusPublished - 8 Nov 2013

Keywords

  • Cannabinoid Receptors
  • Cytoskeleton
  • Endocannabinoids
  • Exocytosis
  • Focal Adhesion Kinase
  • Insulin Release

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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    Malenczyk, K., Jazurek, M., Keimpema, E., Silvestri, C., Janikiewicz, J., Mackie, K., Di Marzo, V., Redowicz, M. J., Harkany, T., & Dobrzyn, A. (2013). CB1 cannabinoid receptors couple to focal adhesion kinase to control insulin release. Journal of Biological Chemistry, 288(45), 32685-32699. https://doi.org/10.1074/jbc.M113.478354