RESUMEN

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.

Asunto(s)

Calcio/metabolismo , Receptor de Adenosina A2A/metabolismo , Receptores de Dopamina D2/metabolismo , Agonistas del Receptor de Adenosina A2/farmacología , Adenilil Ciclasas/metabolismo , Animales , Calmodulina/antagonistas & inhibidores , Calmodulina/genética , Calmodulina/metabolismo , Células Cultivadas , Células HEK293 , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Sensoras del Calcio Neuronal/antagonistas & inhibidores , Proteínas Sensoras del Calcio Neuronal/genética , Proteínas Sensoras del Calcio Neuronal/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuropéptidos/antagonistas & inhibidores , Neuropéptidos/genética , Neuropéptidos/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptor de Adenosina A2A/química , Receptor de Adenosina A2A/genética , Receptores de Dopamina D2/química , Receptores de Dopamina D2/genética , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Transducción de Señal/efectos de los fármacos