An update on adenosine A2A-dopamine D2 receptor interactions: implications for the function of G protein-coupled receptors

Curr Pharm Des. 2008;14(15):1468-74. doi: 10.2174/138161208784480108.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenosine A2 Receptor Agonists
  • Adenosine A2 Receptor Antagonists
  • Adenylyl Cyclases / metabolism
  • Animals
  • Basal Ganglia / physiology
  • Basal Ganglia Diseases / drug therapy
  • Basal Ganglia Diseases / physiopathology
  • Dopamine D2 Receptor Antagonists
  • Enkephalins / metabolism
  • Enzyme Activation
  • GTP-Binding Proteins / physiology
  • Humans
  • Neurons / metabolism
  • Phosphorylation
  • Receptor, Adenosine A2A / physiology*
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / physiology*
  • Substance-Related Disorders / drug therapy
  • Substance-Related Disorders / physiopathology
  • gamma-Aminobutyric Acid / metabolism


  • Adenosine A2 Receptor Agonists
  • Adenosine A2 Receptor Antagonists
  • Dopamine D2 Receptor Antagonists
  • Enkephalins
  • Receptor, Adenosine A2A
  • Receptors, Dopamine D2
  • gamma-Aminobutyric Acid
  • GTP-Binding Proteins
  • Adenylyl Cyclases