Search

G protein–coupled receptors (GPCRs) represent the largest family of plasma membrane proteins targeted for therapeutic development. For decades, GPCRs were investigated as monomeric entities during analysis of their pharmacology or signaling and during drug development. However, a considerable body of evidence now indicates that GPCRs function as dimers or higher-order oligomers. Greater acceptance of oligomerization occurred with the recognition that GPCR interactions form heteromeric receptor complexes, which was validated in vivo, often with pharmacologic, signaling, and functional properties distinct from the constituent protomers. GPCR heteromerization is reviewed in the context of brain disorders, with examples illustrating their functional implication in diverse neuropsychiatric and neurodegenerative disorders, making them an enormous unexploited resource for selective pharmacotherapy target identification. The strategies for development of heteromer-selective ligands are discussed as a new opportunity to precisely target the function of a receptor complex with greater specificity, in contrast to the classical ligands targeting individual receptors. [ABSTRACT FROM AUTHOR]