Recent research in cell signaling has shown that the assembly of G protein coupled receptors into signaling complexes or signalplexes represents the primary mechanism by which receptor-mediated signaling is established and maintained. In this review, we summarize the current state of knowledge regarding protein interactions that comprise the dopamine D2 receptor signalplex within the brain. Studies based on conventional and advanced two-hybrid methodologies, as well as bioinformatic and computational analysis of sequence information from completed genomes have demonstrated interactions between dopamine D2 receptors and a cohort of dopamine receptor interacting proteins (DRIPs). DRIP interactions appear to regulate key aspects of receptor function including the signaling and membrane trafficking of dopamine D2 receptors. Disruptions or modifications of the signalplex, using membrane permeant competing peptide or dominant negative approaches, may represent promising new strategies for the selective targeting of the dopamine D2 receptor in cells and in native tissue. DRIP interactions provide a novel platform for understanding the mechanisms of dopamine receptor signaling, and for the potential development of novel treatments for brain disease.
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