Abstract
The adenosine A2A receptor and the dopamine D2 receptor are prototypically coupled to Gs and Gi/Go, respectively. In striatal intermediate spiny neurons, these receptors are colocalized in dendritic spines and act as mutual antagonists. This antagonism has been proposed to occur at the level of the receptors or of receptor–G protein coupling. We tested this model in PC12 cells which endogenously express A2A receptors. The human D2 receptor was introduced into PC12 cells by stable transfection. A2A-agonist-mediated inhibition of D2 agonist binding was absent in PC12 cell membranes but present in HEK293 cells transfected as a control. However, in the resulting PC12 cell lines, the action of the D2 agonist quinpirole depended on the expression level of the D2 receptor: at low and high receptor levels, the A2A-agonist-induced elevation of cAMP was enhanced and inhibited, respectively. Forskolin-stimulated cAMP formation was invariably inhibited by quinpirole. The effects of quinpirole were abolished by pretreatment with pertussis toxin. A2A-receptor-mediated cAMP formation was inhibited by other Gi/Go-coupled receptors that were either endogenously present (P2y12-like receptor for ADP) or stably expressed after transfection (A1 adenosine, metabotropic glutamate receptor-7A). Similarly, voltage activated Ca2+ channels were inhibited by the endogenous P2Y receptor and by the heterologously expressed A1 receptor but not by the D2 receptor. These data indicate functional segregation of signaling components. Our observations are thus compatible with the proposed model that D2 and A2A receptors are closely associated, but they highlight the fact that this interaction can also support synergism.
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Acknowledgements
We thank Dr E Ogris for a kind gift of antibody 16B12. This work was supported by grants from the Austrian Science Foundation (FWF) and the European Community.
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Kudlacek, O., Just, H., Korkhov, V. et al. The Human D2 Dopamine Receptor Synergizes with the A2A Adenosine Receptor to Stimulate Adenylyl Cyclase in PC12 Cells. Neuropsychopharmacol 28, 1317–1327 (2003). https://doi.org/10.1038/sj.npp.1300181
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DOI: https://doi.org/10.1038/sj.npp.1300181
