jueves, 5 de julio de 2012

Cannabinoid Receptors CB1 and CB2 Form Functional Heteromers in Brain

Cannabinoid Receptors CB1 and CB2 Form Functional Heteromers in Brain

Cannabinoid Receptors CB1 and CB2 Form Functional Heteromers in Brain*

  1. Peter J. McCormick§,2,3
+ Author Affiliations
  1. From the Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain and
  2. the §Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas and
  3. Centro de Investigación Médica Aplicada, Universidad de Navarra, 31008 Pamplona, Spain
  1. 3 A Ramón y Cajal Fellow. To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 643 Avenida Diagonal, planta-2, Barcelona 08028, Spain. Tel.: 934039280; Fax: 934021559; E-mail: pmccormick@ub.edu.
  1. 2 Both authors contributed equally to this work.

Capsule

Background: Although CB1, the most abundant neuronal receptors, and CB2 receptors are co-expressed in neurons, the CB1-CB2 relationship is unknown.
Results: CB1 and CB2 receptors form heteromers in neuronal cells and in the brain.
Conclusion: Activation of either receptor leads to negative modulation of the partner receptor via heteromers.
Significance: These heteromers may explain previous conflicting results and serve as therapeutic targets.

Abstract

Exploring the role of cannabinoid CB2 receptors in the brain, we present evidence of CB2 receptor molecular and functional interaction with cannabinoid CB1 receptors. Using biophysical and biochemical approaches, we discovered that CB2 receptors can form heteromers with CB1 receptors in transfected neuronal cells and in rat brain pineal gland, nucleus accumbens, and globus pallidus. Within CB1-CB2 receptor heteromers expressed in a neuronal cell model, agonist co-activation of CB1 and CB2 receptors resulted in a negative cross-talk in Akt phosphorylation and neurite outgrowth. Moreover, one specific characteristic of CB1-CB2 receptor heteromers consists of both the ability of CB1 receptor antagonists to block the effect of CB2 receptor agonists and, conversely, the ability of CB2 receptor antagonists to block the effect of CB1 receptor agonists, showing a bidirectional cross-antagonism phenomenon. Taken together, these data illuminate the mechanism by which CB2 receptors can negatively modulate CB1 receptor function.

Footnotes

  • 1 A Formación de Profesorado Univesitario Fellow (Grant AP2007-00808).
  • * This work was supported by Spanish Ministerio de Economia and Competitividad Grants SAF2010-18472, SAF2008-03229-E, and SAF2008-03118-E within the framework of the Era-NET Neuron program) and a grant for collaborative projects (Grant PI2011/02-7) from the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED).
  • Received December 24, 2011.
  • Revision received April 15, 2012.

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