Gi protein coupling to adenosine A1-A2A receptor heteromers in human brain caudate nucleus

J Neurochem. 2010 Aug;114(4):972-80. doi: 10.1111/j.1471-4159.2010.06810.x. Epub 2010 May 13.


Pharmacological characterization of adenosine A(1) and A(2A) receptors in human brain caudate nucleus membranes led to non-cooperative binding of radiolabelled ligands. In human caudate nucleus but not in cortex, the agonist binding to A(1) receptors was modulated by the agonist binding to A(2A) receptors indicating a functional negative cross-talk. Accordingly, the A(1) receptor-activation-mediated G(i)-dependent guanosine 5'-o-(3-[(35)S]thio-triphosphate) binding was modulated by agonist binding to A(2A) receptors. A(2A) receptors occupation led to a decrease in the potency of A(1) receptor agonists. These results indicate that A(1) but not A(2A) receptors activation, likely occurring at low adenosine concentrations, engages a G(i)-mediated signaling; however, when both receptors are occupied by adenosine, there is an A(2A) receptor-mediated impairment of G(i)-operated transducing units. These findings are relevant to get insight into the complex relationships derived from co-expression of multiple neurotransmitter/neuromodulator receptors subtypes that individually are coupled to different G proteins. A further finding was the demonstration that the A(2A) receptor agonist, CGS 21680, at high concentrations able to significantly bind to the A(1) receptor, behaved as a partial agonist of the later receptor. This fact might be taken into account when characterizing CGS 21680 actions in human cells expressing A(1) receptors when the compound is used at micromolar concentrations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A1 Receptor Agonists
  • Adenosine A2 Receptor Agonists
  • Binding, Competitive / physiology
  • Caudate Nucleus / drug effects
  • Caudate Nucleus / metabolism*
  • Cell Membrane / metabolism
  • GTP-Binding Protein alpha Subunits, Gi-Go / agonists
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
  • Guanosine 5'-O-(3-Thiotriphosphate) / pharmacology
  • Humans
  • Multiprotein Complexes / agonists
  • Multiprotein Complexes / metabolism*
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Receptor Cross-Talk / physiology*
  • Receptor, Adenosine A1 / metabolism*
  • Receptor, Adenosine A2A / metabolism*


  • Adenosine A1 Receptor Agonists
  • Adenosine A2 Receptor Agonists
  • Multiprotein Complexes
  • Receptor, Adenosine A1
  • Receptor, Adenosine A2A
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • GTP-Binding Protein alpha Subunits, Gi-Go