Molecular determinants of A2AR-D2R allosterism: role of the intracellular loop 3 of the D2R

J Neurochem. 2012 Nov;123(3):373-84. doi: 10.1111/j.1471-4159.2012.07956.x. Epub 2012 Sep 28.


In the CNS, an antagonistic interaction has been shown between adenosine A(2A) and dopamine D(2) receptors (A(2A)Rs and D(2)Rs) that may be relevant both in normal and pathological conditions (i.e., Parkinson's disease). Thus, the molecular determinants mediating this receptor-receptor interaction have recently been explored, as the fine tuning of this target (namely the A(2A)R/D(2)R oligomer) could possibly improve the treatment of certain CNS diseases. Here, we used a fluorescence resonance energy transfer-based approach to examine the allosteric modulation of the D(2)R within the A(2A)R/D(2)R oligomer and the dependence of this receptor-receptor interaction on two regions rich in positive charges on intracellular loop 3 of the D(2)R. Interestingly, we observed a negative allosteric effect of the D(2)R agonist quinpirole on A(2A)R ligand binding and activation. However, these allosteric effects were abolished upon mutation of specific arginine residues (217-222 and 267-269) on intracellular loop 3 of the D(2)R, thus demonstrating a major role of these positively charged residues in mediating the observed receptor-receptor interaction. Overall, these results provide structural insights to better understand the functioning of the A(2A)R/D(2)R oligomer in living cells.

Publication types

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

MeSH terms

  • Adenosine A2 Receptor Agonists / pharmacology
  • Adenosine A2 Receptor Antagonists / pharmacology
  • Allosteric Regulation / drug effects
  • Allosteric Regulation / genetics
  • Arginine / genetics
  • Dopamine Agonists / pharmacology
  • HEK293 Cells
  • Humans
  • Intracellular Fluid / chemistry
  • Intracellular Fluid / drug effects
  • Intracellular Fluid / physiology
  • Mutagenesis, Site-Directed
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Protein Structure, Tertiary / genetics
  • Quinpirole / pharmacology
  • Receptor, Adenosine A2A / chemistry*
  • Receptor, Adenosine A2A / genetics*
  • Receptor, Adenosine A2A / metabolism
  • Receptors, Dopamine D2 / chemistry*
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / physiology*


  • Adenosine A2 Receptor Agonists
  • Adenosine A2 Receptor Antagonists
  • Dopamine Agonists
  • Receptor, Adenosine A2A
  • Receptors, Dopamine D2
  • Quinpirole
  • Arginine