Concurrent Stimulation of Cannabinoid CB1 and Dopamine D2 Receptors Enhances Heterodimer Formation: A Mechanism for Receptor Cross-Talk?

Abstract

Dopamine and endogenous cannabinoids display complex interactions in the basal ganglia. One possible level of interaction is between CB1 cannabinoid and D2 dopamine receptors. Here, we demonstrate that a regulated association of CB1 and D2 receptors profoundly alters CB1 signaling. This provides the first evidence that CB1/D2 receptor complexes exist, are dynamic, and are agonist-regulated with highest complex levels detected when both receptors are stimulated with subsaturating concentrations of agonist. The consequence of this interaction is a differential preference for signaling through a "nonpreferred" G protein. In this case, D2 receptor activation, simultaneously with CB1 receptor stimulation, results in the receptor complex coupling to G␣s protein in preference to the expected G␣i/o proteins. The result of this interaction is an increase in the second messenger cAMP, reversing an initial synergistic inhibition of adenylyl cyclase activity seen at subthreshold concentrations of cannabinoid agonist. Additionally, a pertussis toxin insensitive component in the activation of extracellular signal-regulated kinase (ERK) 1/2 kinases by the cannabinoid agonist CP 55,940 [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol] is revealed in cells stably expressing both CB1 and D2 receptors. Thus, concurrent receptor stimulation promotes a heterooligomeric receptor complex and an apparent shift of CB1 signaling from a pertussis toxin-sensitive inhibition to a partly pertussis toxin-insensitive stimulation of adenylyl cyclase and ERK 1/2 phosphorylation.

Cannabinoid Action Depends on Phosphorylation of Dopamine- and cAMP-Regulated Phosphoprotein of 32 kDa at the Protein Kinase A Site in Striatal Projection Neurons

“…In this regard, it should be noted that stimulation of cAMP accumulation has been shown to occur in striatal neurons after coactivation of CB1 and dopamine D 2 receptors (Glass and Felder, 1997). The mechanism underlying this phenomenon is not clear, but recent evidence shows that heterodimerization with dopamine D 2 receptors is associated with a shift of CB1 receptor signaling from inhibition to stimulation of adenylyl cyclase (Kearn et al, 2005). It is therefore possible that the increase in PKA-catalyzed phosphorylation of DARPP-32 produced by cannabinoids in intact animals is a result of stimulation of postsynaptic CB1 receptors in the presence of tonic activation of dopamine D 2 receptors.…”

Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity

“…This difference could reflect marijuana's agonist properties at cannabinoid 1 (CB1) receptors, which heteromerize with D2 receptors, antagonizing their effects (43). Both CB1 and D2 receptors couple to G i-o proteins and inhibit adenylyl-cyclase, whereas their costimulation results in G s protein-dependent activation of adenylylcyclase (44,45). Moreover, CB1 receptor agonists and antagonists counteract and potentiate, respectively, D2 receptor agonist effects (46)(47)(48)(49), although D2 and CB1 receptor interactions might differ between rodents and primates (50,51).…”

Wiring and firing neuronal networks: endocannabinoids take center stage

“…An increasingly accepted rule is that receptor homo-or heterodimers form functional units of GPCR signaling. The ability of opioid [41], A 2A adenosine [42], and D 2 dopamine receptors [43] to heteromerize with CB 1 Rs provides a mechanism to generate differential G-protein coupling at the CB 1 R, thus directly modulating physiological output. Alternatively, eCB signaling at CB 1 Rs can act as either upstream regulator (transactivation, BDNF/TrkB [25]) or downstream signal effector (N-cadherin/FGF-2 at FGF receptor [38,44]) thereby providing differential control of axonal growth and guidance.…”