Unraveling the Dopamine Receptor Signalplex by DRIPs and DRAPs

In the post-genomic era, the study of G-protein coupled receptor (GPCR)-mediated signal transduction has taken a complicated turn, fueled by the discovery that individual GPCRs are organized within a supramolecular signaling complex termed the signalplex. It has now become clear that a vast amount of cellular information is transmitted via the activity of these multiprotein signaling complexes. In turn, the detailed characterization of several signalplexes has led to a critical re-evaluation of the mechanisms underlying the activation and selectivity of GPCR-mediated signaling within cells. This review examines the role of protein-protein interactions in D2 dopamine receptor (D2R) signaling within the brain. Based on studies utilizing yeast two-hybrid, proteomic, and cell biochemical approaches, the known direct and indirect interactions between D2 receptors and an array of cellular proteins which functionally can be subdivided into scaffolding, cytoskeletal, signaling, receptor, and ion channel molecules, have been summarized. Interactions between signalplex components are found to establish and maintain key aspects of receptor function including the trafficking and assembly of dopamine receptors within various cellular compartments. Understanding the molecular complexity of the D2R signalplex provides a new platform for defining the cellular mechanisms of dopamine signaling in the brain as well as the development of novel drugs for antipsychotic and antiparkinsonian therapy.