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.
Ferré
S
S
National Institute on Drug Abuse, IRP, NIH, DHHS, 5500 Nathan Shock Dr., Baltimore, MD 21224, USA. sferre@intra.nida.nih.gov
Quiroz
C
C
Woods
A S
AS
Cunha
R
R
Popoli
P
P
Ciruela
F
F
Lluis
C
C
Franco
R
R
Azdad
K
K
Schiffmann
S N
SN
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