Adenosine receptor/dopamine receptor interactions : molecular and biochemical aspects

The dopamine receptors have been shown to be involved in a variety of higher brain functions, such as motor control, cognition and affective states. Agonist and antagonists of dopamine receptors are widely used to treat disorders such as Parkinson's disease and schizophrenia, respectively. Adenosine is a well-established neuromodulator in the central nervous system, generally having an inhibitory effect on neural activity, and mediates its effects via adenosine receptors that are widely distributed in the central nervous system. Results from previous studies at all levels from behaviour to biochemical radioligand binding experiments show an antagonistic interaction between adenosine and dopamine receptors. Increasing evidence suggests that antagonistic interactions between specific subtypes of adenosine and dopamine receptors in the basal ganglia are involved in the motor depressant effects of adenosine receptor agonists and the motor stimulant effects of adenosine receptor antagonists, such as caffeine.

The aim of the present studies was to analyse the mechanistic aspects involved in the adenosine A1/dopamine D1 and adenosine A2A/dopamine D2 intramembrane receptor-receptor interactions at the cellular and molecular level. The results from studies with the A1/D1 cell line demonstrated an antagonistic interaction between adenosine A1/dopamine D1 receptors, both at the level of receptor binding and second messengers. Adenosine deaminase (ADA), an enzyme for breaking down adenosine, has recently been shown to be crucial for the high affinity binding state of A, receptors. The results from the present experiments showed that the presence of a structurally intact ADA is important in the A1-D1 interaction, probably by providing the high-affinity state of the A, receptor.

Both A1/D1 and A2A/D2 receptors (but neither A1/D2 nor A2A/D1 receptors)-, were found to coimmunoprecipitate in membrane preparations from cotransfected cell lines, which indicate that A1/D1 and A2A/D2 receptors exist as heteromeric complexes. Moreover, double immunofluorescence experiments with confocal laser microscopy showed a high degree of colocalization between both A1/D1 and A2A/D2 receptors in cell lines and primary cultures. Treatment with adenosine and/or dopamine agonists affected the trafficking of both adenosine and dopamine receptors giving further evidence of functional heteromeric A1/D1 and A2A/D2 complexes. A 3 hour treatment with the D2 agonist induced coaggregation of the A2A and the D2 receptors followed by cointernalization of the two receptors after 15 hours, returning to the baseline level after 24 hours.

A high homology between dopamine D2 and D3 receptors has been shown, and therefore the possible interactions between adenosine A2A receptors and dopamine D3 receptors were studied in an A2A/D3 cell line. The results from binding experiments showed that adenosine A2A and dopamine D3 receptors seem to interact like A2A and D2 receptors at the recognition level, and therefore also A2A/D3 heteromers may exist.

Taken together, the present results give a molecular basis for subtype specific antagonistic adenosine-dopamine receptor interactions involving A1/D1 A2A/D2 and possible A2A/D3 heteromerizations, having implications for treatment of Parkinson's disease and schizophrenia.

List of scientific papers

I. Ferre S, Torvinen M, Antoniou K, Irenius E, Civelli O, Arenas E, Fredholm BB, Fuxe K (1998). Adenosine A1 receptor-mediated modulation of dopamine D1 receptors in stably cotransfected fibroblast cells. J Biol Chem. 273(8): 4718-24.
https://pubmed.ncbi.nlm.nih.gov/9468534

II. Gines S, Hillion J, Torvinen M, Le Crom S, Casado V, Canela EI, Rondin S, Lew JY, Watson S, Zoli M, Agnati LF, Verniera P, Lluis C, Ferre S, Fuxe K, Franco R (2000). Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. Proc Natl Acad Sci U S A. 97(15): 8606-11.
https://pubmed.ncbi.nlm.nih.gov/10890919

III. Torvinen M, Gines S, Hillion J, Latini S, Canals M, Ciruela F, Bordoni F, Staines W, Pedata F, Agnati LF, Lluis C, Franco R, Ferre S, Fuxe K (2002). Interactions among adenosine deaminase, adenosine A(1) receptors and dopamine D(1) receptors in stably cotransfected fibroblast cells and neurons. Neuroscience. 113(3): 709-19.
https://pubmed.ncbi.nlm.nih.gov/12150791

IV. Hillion J, Canals M, Torvinen M, Casado V, Scott R, Terasmaa A, Hansson A, Watson S, Olah ME, Mallol J, Canela EI, Zoli M, Agnati LF, Ibanez CF, Lluis C, Franco R, Ferre S, Fuxe K (2002). Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J Biol Chem. 277(20): 18091-7.
https://pubmed.ncbi.nlm.nih.gov/11872740

V. Torvinen M, Torri C, Tombesi A, Watson S, Franco R, Fuxe K, Agnati L (2002). Agonist and antagonist regulation of adenosine A2A and dopamine D2 receptor cotrafficking. [Manuscript]

VI. Torvinen M, Kozell L, Neve K, Ibanez C, Fuxe K (2002). Intarmembrane interactions between adenosine A2A and dopamine D3 receptors and adenosine A2a/chimeric D2/D1 receptors. A biochemical binding study. [Manuscript]