Cannabinoid receptors CB 1 and CB 2 form functional heteromers in brain

Abstract

Exploring the role of cannabinoid CB 2 receptors in the brain, we present evidence of CB 2 receptor molecular and functional interaction with cannabinoid CB 1 receptors. Using biophysical and biochemical approaches, we discovered that CB 2 receptors can form heteromers with CB 1 receptors in transfected neuronal cells and in rat brain pineal gland, nucleus accumbens, and globus pallidus. Within CB 1-CB 2 receptor heteromers expressed in a neuronal cell model, agonist co-activation of CB 1and CB 2 receptors resulted in a negative cross-talk in Akt phosphorylation and neurite outgrowth. Moreover, one specific characteristic of CB 1-CB 2 receptor heteromers consists of both the ability of CB 1 receptor antagonists to block the effect of CB 2receptor agonists and, conversely, the ability of CB 2 receptor antagonists to block the effect of CB 1 receptor agonists, showing a bidirectional cross-antagonism phenomenon. Taken together, these data illuminate the mechanism by which CB 2 receptors can negatively modulate CB 1 receptor function. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.