A proteomic approach to receptor signaling: Molecular mechanisms and therapeutic implications derived from discovery of the dopamine D₂ receptor signalplex

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.