Coaggregation, cointernalization, and codesensitization of adenosine A_2A receptors and dopamine D₂ receptors

Antagonistic and reciprocal interactions are known to exist between adenosine and dopamine receptors in the striatum. In the present study, double immunofluorescence experiments with confocal laser microscopy showed a high degree of colocalization of adenosine A_2A receptors (A_2AR) and dopamine D₂ receptors (D₂R) in cell membranes of SH-SY5Y human neuroblastoma cells stably transfected with human D₂R and in cultured striatal cells. A_2AR/D₂R heteromeric complexes were demonstrated in coimmunoprecipitation experiments in membrane preparations from D₂R-transfected SH-SY5Y cells, and from mouse fibroblast Ltk- cells stably transfected with human D₂R (long form) and transiently cotransfected with the A_2AR double-tagged with hemagglutinin. Long term exposure to A_2AR and D₂R agonists in D₂R-cotransfected SH-SY5Y cells resulted in coaggregation, cointernalization and codesensitization of A_2AR and D₂R. These results give a molecular basis for adenosine-dopamine antagonism at the membrane level and have implications for treatment of Parkinson's disease and schizophrenia, in which D₂R are involved.