title: Cannabinoids induce pancreatic β-cell death by directly inhibiting insulin receptor activation.
abstract: Cannabinoid 1 (CB1) receptors have been previously detected in pancreatic β cells, where they attenuate insulin action. We now report that CB1 receptors form a heteromeric complex with insulin receptors and the heterotrimeric guanosine triphosphate-binding protein α subunit Gα(i). Gα(i) inhibited the kinase activity of the insulin receptor in β cells by directly binding to the activation loop in the tyrosine kinase domain of the receptor. Consequently, phosphorylation of proapoptotic protein Bad was reduced and its apoptotic activity was stimulated, leading to β-cell death. Pharmacological blockade or genetic deficiency of CB1 receptors enhanced insulin receptor signaling after injury, leading to reduced blood glucose concentrations and activation of Bad, which increased β-cell survival. These findings provide direct evidence of physical and functional interactions between CB1 and insulin receptors and suggest a mechanism whereby peripherally acting CB1 receptor antagonists improve insulin action in insulin-sensitive tissues independent of the other metabolic effects of CB1 receptors.
authors.affiliation: National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Wook
authors.initials: W
authors.lastname: Kim
authors.forename: Qizong
authors.initials: Q
authors.lastname: Lao
authors.forename: Yu-Kyong
authors.initials: YK
authors.lastname: Shin
authors.forename: Olga D
authors.initials: OD
authors.lastname: Carlson
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Lee
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Egan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002186:Cannabinoids / Q000494:pharmacology*; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: C494819:BAD protein, human; D002186:Cannabinoids; D061945:Caspase Inhibitors; D018076:DNA, Complementary; D043884:Receptor, Cannabinoid, CB1; D051025:bcl-Associated Death Protein; D011972:Receptor, Insulin