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Receptor heteromerization in adenosine A_2A receptor signaling

Relevance for striatal function and Parkinson’s disease

From the Department of Neuroscience (Drs. Fuxe, Torvinen, and Terasmaa), Karolinska Institute, Stockholm, Sweden; Biomedical Sciences (Drs. Agnati, Leo, and Vergoni), University of Modena, Italy; Department of Anatomy (Dr. Staines, K. Jacobsen and B. Tinner-Staines), University of Ottawa, Canada; Stroke Branch (Dr. Hillion), NINDS, NIH, Bethesda, MD; Department of Biochemistry and Molecular Biology (Drs. Lluis, Ciruela, and Franco, M. Canals), University of Barcelona, Spain; Department of Pharmacology (Dr. Rosin), University of Virginia Health Sciences Center, Charlottesville, VA; Department of Pharmacology (Dr. Popoli), Istituto Superiore di Sanita, Rome, Italy; and Pre-clinical Pharmacology Section (Dr. Ferré), Behavioral Neuroscience Branch, NIDA, NIH, IRP, Baltimore, MD.

Address correspondence and reprint requests to Dr. Kjell Fuxe, Department of Neuroscience, Karolinska Institutet, Retzius väg 8, A2:4, S17177, Stockholm, Sweden; e-mail: kjell.fuxe{at}neuro.ki.se

Recently evidence has been presented that adenosine A_2A and dopamine D₂ receptors form functional heteromeric receptor complexes as demonstrated in human neuroblastoma cells and mouse fibroblast Ltk^- cells. These A_2A/D₂ heteromeric receptor complexes undergo coaggregation, cointernalization, and codesensitization on D₂ or A_2A receptor agonist treatments and especially after combined agonist treatment. It is hypothesized that the A_2A/D₂ receptor heteromer represents the molecular basis for the antagonistic A_2A/D₂ receptor interactions demonstrated at the biochemical and behavioral levels. Functional heteromeric complexes between A_2A and metabotropic glutamate 5 receptors (mGluR5) have also recently been demonstrated in HEK-293 cells and rat striatal membrane preparations. The A_2A/mGluR5 receptor heteromer may account for the synergism found after combined agonist treatments demonstrated in different in vitro and in vivo models. D₂, A_2A, and mGluR5 receptors are found together in the dendritic spines of the striatopallidal GABA neurons. Therefore, possible D₂/A_2A/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.

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