Cannabinoid Receptors CB1 and CB2 Form Functional Heteromers in Brain

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