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

Navarro, Gemma, Aguinaga, David, Moreno, Estefania, Hradsky, Johannes, Reddy, Pasham P., Cortés, Antoni, Mallol, Josefa, Casadó, Vicent, Mikhaylova, Marina, Kreutz, Michael R., Lluís, Carme, Canela, Enric I., McCormick, Peter J. and Ferré, Sergi (2014) Intracellular calcium levels determine differential modulation of allosteric interactions within G protein-coupled receptor heteromers. Chemistry & Biology, 21 (11). pp. 1546-1556. ISSN 1074-5521

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Abstract

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.

Item Type:	Article
Faculty \ School:	Faculty of Science > School of Pharmacy
Depositing User:	Pure Connector
Date Deposited:	12 Nov 2014 16:38
Last Modified:	16 Apr 2024 13:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/50887
DOI:	10.1016/j.chembiol.2014.10.004

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