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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine A2 Receptor Agonists / pharmacology
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Adenylyl Cyclases / metabolism
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Animals
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Calcium / metabolism*
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Calmodulin / antagonists & inhibitors
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Calmodulin / genetics
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Calmodulin / metabolism
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Cells, Cultured
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HEK293 Cells
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Humans
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mitogen-Activated Protein Kinases / metabolism
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Neuronal Calcium-Sensor Proteins / antagonists & inhibitors
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Neuronal Calcium-Sensor Proteins / genetics
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Neuronal Calcium-Sensor Proteins / metabolism
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism
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Neuropeptides / antagonists & inhibitors
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Neuropeptides / genetics
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Neuropeptides / metabolism
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Phosphorylation / drug effects
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Rats
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Rats, Sprague-Dawley
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Receptor, Adenosine A2A / chemistry
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Receptor, Adenosine A2A / genetics
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Receptor, Adenosine A2A / metabolism*
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Receptors, Dopamine D2 / chemistry
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Receptors, Dopamine D2 / genetics
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Receptors, Dopamine D2 / metabolism*
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Recombinant Fusion Proteins / biosynthesis
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / genetics
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Signal Transduction / drug effects
Substances
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Adenosine A2 Receptor Agonists
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CALN1 protein, human
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Calmodulin
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Neuronal Calcium-Sensor Proteins
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Neuropeptides
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Receptor, Adenosine A2A
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Receptors, Dopamine D2
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Recombinant Fusion Proteins
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frequenin calcium sensor proteins
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Adenylyl Cyclases
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Calcium