Gemma Navarro, David Aguinaga, Estefania Moreno, Johannes Hradsky, Pasham P. Reddy, Antoni Cortés, Josefa Mallol, Vicent Casadó, Marina Mikhaylova, Michael R. Kreutz, Carme Lluís, Enric I. Canela, Peter J. McCormick, Sergi Ferré

The pharmacological significance of the adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromer is well established and it is being considered as an important target for the treatment of Parkinson's disease and other neuropsychiatric disorders. However, the physiological factors that control its distinctive biochemical properties are still unknown. We demonstrate that different intracellular Ca(2+) levels exert a differential modulation of A2AR-D2R heteromer-mediated adenylyl-cyclase and MAPK signaling in striatal cells. This depends on the ability of low and high Ca(2+) levels to promote a selective interaction of the heteromer with the neuronal Ca(2+)-binding proteins NCS-1 and calneuron-1, respectively. These Ca(2+)-binding proteins differentially modulate allosteric interactions within the A2AR-D2R heteromer, which constitutes a unique cellular device that integrates extracellular (adenosine and dopamine) and intracellular (Ca(+2)) signals to produce a specific functional response.