Intracellular calcium levels determine differential modulation of allosteric interactions within G protein-coupled receptor heteromers

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

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


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 Ca2+ 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 Ca2+ levels to promote a selective interaction of the heteromer with the neuronal Ca2+-binding proteins NCS-1 and calneuron-1, respectively. These Ca2+-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.
Original languageEnglish
Pages (from-to)1546-1556
Number of pages11
JournalChemistry & Biology
Issue number11
Early online date6 Nov 2014
Publication statusPublished - 20 Nov 2014

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