- Beta-arrestins uncouple G protein-coupled receptors (GPCRs) from G proteins and promote their internalization, leading to desensitization and downregulation and serving as negative regulators of GPCR signaling. beta-Arrestins also function as scaffold proteins, interacting with several cytoplasmic proteins and linking GPCRs to intracellular signaling pathways such as the mitogen-activated protein kinase (MAPK) cascade. Recent work has also revealed that beta-arrestins translocate from the cytoplasm to the nucleus and associate with transcription factors such as histone acetyltransferase p300 and cyclic adenosine monophosphate (cAMP)-responsive element-binding protein. These substances also interact with regulators of transcription factors. We review findings on the effects of antidepressants on beta-arrestins and the plethora of antidepressant effects on signal transduction elements in which beta-arrestins serve as signaling scaffold proteins, focusing on the three major groups of MAPKs: extracellular signal-regulated kinases, c-Jun N-terminal kinases and p38 MAPKs, and on transcription factors and cofactors of which beta-arrestins mediate transcription regulation.