Antidepressants, β-Arrestins and GRKs: From Regulation of Signal Desensitization to Intracellular Multifunctional Adaptor Functions
G protein-coupled receptors (GPCR) have generated considerable interest in the pharmaceutical industry as drug targets. Theories concerning antidepressant targets of action suggested pre-synaptic monoamine reuptake mechanisms regulating GPCR activities including delayed receptor desensitization and down-regulation. GRKs and β-arrestins translocate to the cell membrane and bind to agonist-occupied receptors. This uncouples these receptors from G proteins and promotes their internalization, leading to desensitization and down-regulation. Thus, GRKs and β-arrestins serve as negative regulators of GPCR signaling. Recently, GPCR have been demonstrated to elicit signals through interaction with β-arrestin as scaffolding proteins, independent of heterotrimeric G-protein coupling. β-arrestins function as scaffold proteins that interact with several cytoplasmic proteins and link GPCR to intracellular signaling pathways such as MAPK cascades. Recent work has also revealed that β-arrestins translocate from the cytoplasm to the nucleus and associatewith transcription cofactors such as p300 and CREB. They also interact with regulators of transcription factors. We review findings concerning effects of antidepressants on GRKs and β-arrestins and the plethora of antidepressants effects on signal transduction elements in which GRKs and β-arrestins serve as signaling scaffold proteins, and on transcription factors and cofactors in which β-arrestins mediate regulation of transcription. The emergence of G-protein-independent signaling pathways, through β-arrestins, changes the way in which GPCR signaling is evaluated, from a cell biological to a pharmaceutical perspective and raises the possibility for the development of pathway specific therapeutics e.g., antidepressant medications targeting GRKs and β-arrestin regulatory and signaling proteins.
Keywords: mood disorders, antidepressants, GPCR, GRK, β-arrestin
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