Adenosine A2A-dopamine D2 receptor–receptor heteromers. Targets for neuro-psychiatric disorders

https://doi.org/10.1016/j.parkreldis.2004.02.014Get rights and content

Abstract

Emerging evidence shows that G protein-coupled receptors can form homo- and heteromers. These include adenosine A2A receptor–dopamine D2 receptor heteromers, which are most probably localized in the dendritic spines of the striatopallidal GABAergic neurons, where they are in a position to modulate glutamatergic neurotransmission. The discovery of A2A receptor–dopamine D2 receptor heteromers gives a frame for the well-known antagonistic interaction between both receptors, which is the bases for a new therapeutic approach for neuro-psychiatric disorders, such as Parkinson's disease and schizoprenia. The present review deals mainly with the biochemical and molecular aspects of A2A receptor–dopamine D2 receptor interactions. Recent results at the molecular level show that A2A receptor–dopamine D2 receptor heteromers represent the first example of epitope–epitope electrostatic interaction underlying receptor heteromerization. Most probably A2A receptor–D2 receptor heteromerization is not static, but subject to a dynamic regulation, related to the phosphorylation dependence of the A2A receptor epitope and to the ability of the D2 receptor epitope to bind different partners. Finding out the mechanisms involved in this dynamic regulation can have important implications for the treatment of basal ganglia disorders, schizophrenia and drug addiction.

Section snippets

G protein-coupled receptor heteromerization

G protein-coupled receptors (GPCRs; and also ligand gated ion channels) cannot any longer be considered as single units, but as being part of multimolecular aggregates. In most instances, GPCRs are functionally connected with other molecules either intrinsic to the plasma membrane or associated with the extracellular or intracellular surfaces of the membrane. The function of each GPCR can be markedly affected by its interactions with these other molecules, especially proteins. By means of these

Adenosine A2A and dopamine D2 receptors in the dendritic spines of the striopallidal neuron

The striatum is the main input structure of the basal ganglia and is functionally subdivided in dorsal and ventral striatum. The dorsal striatum is involved in the performance and learning of complex motor acts. The ventral striatum forms part of brain circuits involved in the conversion of motivation into action, into the selection of appropriate behavioral responses elicited by specific motivational stimuli. Learning of complex motor acts and association of motivationally significant stimuli

Interactions between adenosine A2A and dopamine D2 receptors at the biochemical level

At the biochemical level, it was initially shown that, in crude membrane preparations from rat striatum, stimulation of A2A receptors produces a decrease in the affinity of D2 receptors for agonists [24]. This intramembrane interaction implied that stimulation of A2A receptor produces some kind of steric modification of the D2 receptor, with the concomitant change in its binding properties. It was postulated that this A2A receptor–D2 receptor interaction requires a close proximity between both

Direct protein–protein interaction between adenosine A2A and dopamine D2 receptors

The first indication for the possible existence of direct proteins–protein interactions between A2A and D2 receptors was the demonstration of the intramembrane A2A receptor–D2 receptor interaction in radioligand-binding experiments (see above). Recently coimmunoprecipitation of both receptors was demonstrated in the D2 receptor-transfected human neuroblastoma SH-SY5Y cell line and in a mouse fibroblast Ltk- cell line stably transfected with D2 receptors and transiently cotransfected with A2A

References (49)

  • L Yao et al.

    Betagamma Dimers mediate synergy of dopamine D2 and adenosine A2 receptor-stimulated PKA signaling and regulate ethanol consumption

    Cell

    (2002)
  • M Canals et al.

    Adenosine A2A–dopamine D2 receptor–receptor heteromerization. Qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer

    J Biol Chem

    (2003)
  • A.S Woods et al.

    A study of peptide–peptide interaction by matrix-assisted laser desorption/ionization

    J Am Soc Mass Spectrom

    (2001)
  • A.S Woods et al.

    A study of peptide–peptide interactions using MALDI ion mobility o-TOF and ESI mass spectrometry

    J Am Soc Mass Spectrom

    (2002)
  • F Liu et al.

    Mechanism of regulation of casein kinase I activity by group I metabotropic glutamate receptors

    J Biol Chem

    (2002)
  • S Ferré et al.

    Adenosine A2A and group I metabotropic glutamate receptors synergistically modulate the binding characteristics of dopamine D2 receptors in the rat striatum

    Neuropharmacology

    (1999)
  • P Popoli et al.

    The selective mGlu(5) receptor agonist CHPG inhibits quinpirole-induced turning in 6-hydroxydopamine-lesioned rats and modulates the binding characteristics of dopamine D(2) receptors in the rat striatum: interactions with adenosine A(2a) receptors

    Neuropsychopharmacology

    (2001)
  • L.F Agnati et al.

    Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons

    Pharmacol Rev

    (2003)
  • L.F Agnati et al.

    Possible role of intramembrane receptor–receptor interactions in memory and learning via formation of long-lived heteromeric complexes: focus on motor learning in the basal ganglia

    J Neural Transm Suppl

    (2003)
  • S Ferré et al.

    Glutamate mGlu5-adenosine A2A–dopamine D2 receptor interactions in the striatum. Implications for drug therapy in neuro-psychiatric disorders and drug abuse

    Curr Med Chem—Central Nervous System Agents

    (2003)
  • M Zoli et al.

    Receptor–receptor interactions as an integrative mechanism in nerve cells

    Mol Neurobiol

    (1993)
  • M Bouvier

    Oligomerization of G-protein-coupled transmitter receptors

    Nat Rev Neurosci

    (2001)
  • S Ferré

    Adenosine–dopamine interactions in the ventral striatum. Implications for the treatment of schizophrenia

    Psychopharmacology

    (1997)
  • L Heimer et al.

    Basal ganglia

  • Cited by (132)

    • Cocaine Addiction and Adenosine A1 and A2A Receptors

      2017, The Neuroscience of Cocaine: Mechanisms and Treatment
    View all citing articles on Scopus
    View full text