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

doi:10.1016/j.chembiol.2014.10.004

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 journal › Article › peer-review

45 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1546-1556
Number of pages	11
Journal	Chemistry & Biology
Volume	21
Issue number	11
Early online date	6 Nov 2014
DOIs	https://doi.org/10.1016/j.chembiol.2014.10.004
Publication status	Published - 20 Nov 2014

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10.1016/j.chembiol.2014.10.004

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Navarro, G., Aguinaga, D., Moreno, E., Hradsky, J., Reddy, P. P., Cortés, A., Mallol, J., Casadó, V., Mikhaylova, M., Kreutz, M. R., Lluís, C., Canela, E. I., McCormick, P. J., & Ferré, S. (2014). Intracellular calcium levels determine differential modulation of allosteric interactions within G protein-coupled receptor heteromers. Chemistry & Biology, 21(11), 1546-1556. https://doi.org/10.1016/j.chembiol.2014.10.004

@article{22b48b6ea15e49e3b223fc50a5b78f0f,

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

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{\textquoteright}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.",

author = "Gemma Navarro and David Aguinaga and Estefania Moreno and Johannes Hradsky and Reddy, {Pasham P.} and Antoni Cort{\'e}s and Josefa Mallol and Vicent Casad{\'o} and Marina Mikhaylova and Kreutz, {Michael R.} and Carme Llu{\'i}s and Canela, {Enric I.} and McCormick, {Peter J.} and Sergi Ferr{\'e}",

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Navarro, G, Aguinaga, D, Moreno, E, Hradsky, J, Reddy, PP, Cortés, A, Mallol, J, Casadó, V, Mikhaylova, M, Kreutz, MR, Lluís, C, Canela, EI, McCormick, PJ & Ferré, S 2014, 'Intracellular calcium levels determine differential modulation of allosteric interactions within G protein-coupled receptor heteromers', Chemistry & Biology, vol. 21, no. 11, pp. 1546-1556. https://doi.org/10.1016/j.chembiol.2014.10.004

TY - JOUR

T1 - Intracellular calcium levels determine differential modulation of allosteric interactions within G protein-coupled receptor heteromers

AU - Navarro, Gemma

AU - Aguinaga, David

AU - Moreno, Estefania

AU - Hradsky, Johannes

AU - Reddy, Pasham P.

AU - Cortés, Antoni

AU - Mallol, Josefa

AU - Casadó, Vicent

AU - Mikhaylova, Marina

AU - Kreutz, Michael R.

AU - Lluís, Carme

AU - Canela, Enric I.

AU - McCormick, Peter J.

AU - Ferré, Sergi

PY - 2014/11/20

Y1 - 2014/11/20

N2 - 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.

AB - 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.

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DO - 10.1016/j.chembiol.2014.10.004

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JO - Chemistry & Biology

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