An update on adenosine A_2A-dopamine D₂ receptor interactions: Implications for the function of G protein-coupled receptors

Adenosine A_2A-dopamine D₂ receptor interactions play a very important role in striatal function. A_2A-D₂ receptor interactions provide an example of the capabilities of information processing by just two different G protein-coupled receptors. Thus, there is evidence for the coexistence of two reciprocal antagonistic interactions between A_2A and D₂ receptors in the same neurons, the GABAergic enkephalinergic neurons. An antagonistic A_2A-D₂ intrumembrane receptor interaction, which depends on A_2A-D₂ receptor heteromerization and G_q/₁₁-PLC signaling, modulates neuronal excitability and neurotransmitter release. On the other hand, an antagonistic A_2A-D₂ receptor interaction at the adenylyl-cyclase level, which depends an G_g/olf- and G_l/o type V adenylyl-cyclase signaling, modulates protein phosphorylation and gene expression. Finally, under conditions of upregulation of an activator of G protein signaling (AGS3), such as during chronic treatment with addictive drugs, a synergistic A_2A-D₂ receptor interaction can also be demonstrated. AGS3 facilitates a synergistic interaction between G_{g/ olf} - and G_i/o-coupled receptors on the activation of types II/IV adenylyl cyclase, leading to a paradoxical increase in protein phosphorylation and gene expression upon co-activation of A_2A and D₂ receptors. The analysis A₂-D₂ receptor interactions will have implications for the pathophysiology and treatment of basal ganglia disorders and drug addiction.