An update on adenosine A2A-dopamine D2 receptor interactions: implications for the function of G protein-coupled receptors.
Adenosine A(2A)-dopamine D(2) receptor interactions play a very important role in striatal function. A(2A)-D(2) 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 D(2) receptors in the same neurons, the GABAergic enkephalinergic neurons. An antagonistic A(2A)-D(2) intramembrane receptor interaction, which depends on A(2A)-D(2) receptor heteromerization and G(q/11)-PLC signaling, modulates neuronal excitability and neurotransmitter release. On the other hand, an antagonistic A(2A)-D(2) receptor interaction at the adenylyl-cyclase level, which depends on G(s/olf)- and G(i/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)-D(2) receptor interaction can also be demonstrated. AGS3 facilitates a synergistic interaction between G(s/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 D(2) receptors. The analysis of A(2)-D(2) receptor interactions will have implications for the pathophysiology and treatment of basal ganglia disorders and drug addiction.
National Institute on Drug Abuse, IRP, NIH, DHHS, 5500 Nathan Shock Dr., Baltimore, MD 21224, USA. sferre@intra.nida.nih.gov
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D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001479:Basal Ganglia / Q000502:physiology; D001480:Basal Ganglia Diseases / Q000188:drug therapy / Q000503:physiopathology; D065127:Dopamine D2 Receptor Antagonists; D004745:Enkephalins / Q000378:metabolism; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology*; D019966:Substance-Related Disorders / Q000188:drug therapy / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D065127:Dopamine D2 Receptor Antagonists; D004745:Enkephalins; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D005680:gamma-Aminobutyric Acid; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases