Antidepressants, beta-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 beta-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 beta-arrestins serve as negative regulators of GPCR signaling. Recently, GPCR have been demonstrated to elicit signals through interaction with beta-arrestin as scaffolding proteins, independent of heterotrimeric G-protein coupling. beta-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 beta-arrestins translocate from the cytoplasm to the nucleus and associate with 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 beta-arrestins and the plethora of antidepressants effects on signal transduction elements in which GRKs and beta-arrestins serve as signaling scaffold proteins, and on transcription factors and cofactors in which beta-arrestins mediate regulation of transcription. The emergence of G-protein-independent signaling pathways, through beta-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 beta-arrestin regulatory and signaling proteins.
Departments of Pharmacology, University of the Negev Beer Sheva Israel, and Barzilai Medical Center, Ashkelon, Israel.
Moran
M
Golan
Gabriel
G
Schreiber
Sofia
S
Avissar
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D019390:Arrestins / Q000187:drug effects / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology; D016503:Drug Delivery Systems; D054768:G-Protein-Coupled Receptor Kinases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D000071557:beta-Arrestins
D000928:Antidepressive Agents; D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; D054768:G-Protein-Coupled Receptor Kinases