Adenosine A2A-dopamine D2 receptor–receptor heteromers. Targets for neuro-psychiatric disorders
Section snippets
G protein-coupled receptor heteromerization
G protein-coupled receptors (GPCRs; and also ligand gated ion channels) cannot any longer be considered as single units, but as being part of multimolecular aggregates. In most instances, GPCRs are functionally connected with other molecules either intrinsic to the plasma membrane or associated with the extracellular or intracellular surfaces of the membrane. The function of each GPCR can be markedly affected by its interactions with these other molecules, especially proteins. By means of these
Adenosine A2A and dopamine D2 receptors in the dendritic spines of the striopallidal neuron
The striatum is the main input structure of the basal ganglia and is functionally subdivided in dorsal and ventral striatum. The dorsal striatum is involved in the performance and learning of complex motor acts. The ventral striatum forms part of brain circuits involved in the conversion of motivation into action, into the selection of appropriate behavioral responses elicited by specific motivational stimuli. Learning of complex motor acts and association of motivationally significant stimuli
Interactions between adenosine A2A and dopamine D2 receptors at the biochemical level
At the biochemical level, it was initially shown that, in crude membrane preparations from rat striatum, stimulation of A2A receptors produces a decrease in the affinity of D2 receptors for agonists [24]. This intramembrane interaction implied that stimulation of A2A receptor produces some kind of steric modification of the D2 receptor, with the concomitant change in its binding properties. It was postulated that this A2A receptor–D2 receptor interaction requires a close proximity between both
Direct protein–protein interaction between adenosine A2A and dopamine D2 receptors
The first indication for the possible existence of direct proteins–protein interactions between A2A and D2 receptors was the demonstration of the intramembrane A2A receptor–D2 receptor interaction in radioligand-binding experiments (see above). Recently coimmunoprecipitation of both receptors was demonstrated in the D2 receptor-transfected human neuroblastoma SH-SY5Y cell line and in a mouse fibroblast Ltk- cell line stably transfected with D2 receptors and transiently cotransfected with A2A
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