Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 20 March 2012
Vol. 5, Issue 216, p. ra23
[DOI: 10.1126/scisignal.2002519]

RESEARCH ARTICLES

Cannabinoids Induce Pancreatic β-Cell Death by Directly Inhibiting Insulin Receptor Activation

Wook Kim1, Qizong Lao1, Yu-Kyong Shin1, Olga D. Carlson1, Eun Kyung Lee2, Myriam Gorospe1, Rohit N. Kulkarni3, and Josephine M. Egan1*

1 National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
2 Department of Biochemistry, College of Medicine, Catholic University of Korea, Seoul 137-701, Republic of Korea.
3 Department of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.

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 Gαi. Gαi 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.

* To whom correspondence should be addressed. E-mail: eganj{at}grc.nia.nih.gov

Citation: W. Kim, Q. Lao, Y.-K. Shin, O. D. Carlson, E. K. Lee, M. Gorospe, R. N. Kulkarni, J. M. Egan, Cannabinoids Induce Pancreatic β-Cell Death by Directly Inhibiting Insulin Receptor Activation. Sci. Signal. 5, ra23 (2012).

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
CB1 Cannabinoid Receptors Couple to Focal Adhesion Kinase to Control Insulin Release.
K. Malenczyk, M. Jazurek, E. Keimpema, C. Silvestri, J. Janikiewicz, K. Mackie, V. Di Marzo, M. J. Redowicz, T. Harkany, and A. Dobrzyn (2013)
J. Biol. Chem. 288, 32685-32699
   Abstract »    Full Text »    PDF »
Metabolic Effects of Chronic Cannabis Smoking.
R. Muniyappa, S. Sable, R. Ouwerkerk, A. Mari, A. M. Gharib, M. Walter, A. Courville, G. Hall, K. Y. Chen, N. D. Volkow, et al. (2013)
Diabetes Care 36, 2415-2422
   Abstract »    Full Text »    PDF »
Human {beta}-Cell Proliferation and Intracellular Signaling: Driving in the Dark Without a Road Map.
R. N. Kulkarni, E.-B. Mizrachi, A. G. Ocana, and A. F. Stewart (2012)
Diabetes 61, 2205-2213
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882