Receptor heteromerization in adenosine A2A receptor signaling: relevance for striatal function and Parkinson's disease.

Recently evidence has been presented that adenosine A2A and dopamine D2 receptors form functional heteromeric receptor complexes as demonstrated in human neuroblastoma cells and mouse fibroblast Ltk- cells. These A2A/D2 heteromeric receptor complexes undergo coaggregation, cointernalization, and codesensitization on D2 or A2A receptor agonist treatments and especially after combined agonist treatment. It is hypothesized that the A2A/D2 receptor heteromer represents the molecular basis for the antagonistic A2A/D2 receptor interactions demonstrated at the biochemical and behavioral levels. Functional heteromeric complexes between A2A and metabotropic glutamate 5 receptors (mGluR5) have also recently been demonstrated in HEK-293 cells and rat striatal membrane preparations. The A2A/mGluR5 receptor heteromer may account for the synergism found after combined agonist treatments demonstrated in different in vitro and in vivo models. D2, A2A, and mGluR5 receptors are found together in the dendritic spines of the striatopallidal GABA neurons. Therefore, possible D2/A2A/mGluR5 multimeric receptor complexes and the receptor interactions within them may have a major role in controlling the dorsal and ventral striatopallidal GABA neurons involved in Parkinson's disease and in schizophrenia and drug addiction, respectively.

Adenosine A1 receptor-dopamine D1 receptor interaction in the rat limbic system: modulation of dopamine D1 receptor antagonist binding sites.

Antagonistic interactions between adenosine A2a and dopamine D2 receptors and between adenosine A1 and dopamine D1 receptors have been previously found in the basal ganglia. Those interactions have been proposed to be key mechanisms of action responsible for the motor depressant effects of adenosine agonists and the motor activating effects of adenosine antagonists, like caffeine. By using quantitative receptor autoradiography, the selective adenosine A1 receptor agonist N6-cyclopentyladenosine was found to decrease the affinity of dopamine D1 receptors for the specific D1 antagonist [(125)I]SCH 23982 in both the nucleus accumbens and the medial prefrontal cortex of the rat brain. The present results suggest that dopamine neurotransmission, through an A1-D1 interaction, might also he involved in the behavioural effects of adenosine agonists and antagonists not related to motor activity, like the sedative-hypnogenic properties of adenosine analogues and the psychostimulant effects of caffeine.