β-arrestin signaling and regulation of transcription

Abstract

β-arrestin 1 and β-arrestin 2 are well-known negative regulators of G-protein-coupled receptor (GPCR) signaling. Upon GPCR activation, β-arrestins translocate to the cell membrane and bind to the agonist-occupied receptors. This uncouples these receptors from G proteins and promotes their internalization, thus causing desensitization. However, accumulating evidence indicates that β-arrestins also function as scaffold proteins that interact with several cytoplasmic proteins and link GPCRs to intracellular signaling pathways such as MAPK cascades. Recent work has also revealed that, in response to activation of certain GPCRs, β-arrestins translocate from the cytoplasm to the nucleus and associate with transcription cofactors such as p300 and cAMP-response element-binding protein (CREB) at the promoters of target genes to promote transcription. They also interact with regulators of transcription factors, such as IκBα and MDM2, in the cytoplasm and regulate transcription indirectly. This β-arrestin-mediated regulation of transcription appears to play important roles in cell growth, apoptosis and modulation of immune functions.

Norepinephrine Controls Effector T Cell Differentiation through β2-Adrenergic Receptor–Mediated Inhibition of NF-κB and AP-1 in Dendritic Cells

“…More recently, it was also demonstrated that b-arrestin 1 and 2 interact with IkBa (24). This interaction prevents phosphorylation and degradation of IkBa and, thus, inhibits NF-kB translocation to the cell nucleus and attenuates the transcription of NF-kB target genes (23,24,36). In addition, b 2 AR stimulation significantly increases the amount of b-arrestin 2 that is associated with IkBa, which stabilizes IkBa and decreases TNF-a-induced phosphorylation and degradation of endogenous IkBa, with a consequent reduction in the expression of NF-kB target genes, such as IL-6 and IL-8 (23).…”

Expression changes in arrestin β 1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients

“…In this study, we found that ARRB1 mRNA expression is a reproducible and useful biomarker for monitoring the effects of morphine treatment using PBLs as surrogate tissues. ARRB1 regulates the desensitization of numerous GPCRs including OPRM1, D1 and D2 dopamine receptors and emerging evidence has demonstrated that ARRB1 functions as a scaffold protein that links GPCRs to intracellular signaling, such as MAPK and as a transcription factor that translocates to the nucleus (16,17). A recent study showed that chronic morphine treatment blocked the agonist-induced redistribution of ARRB1 in stably OPRM1-transfected HEK293 cells through the persistent stimulation of MAPK activity and the authors concluded that chronic morphine treatment produces adaptational changes at the ARRB1 level (18).…”

Fenoterol, a β2-adrenoceptor agonist, inhibits LPS-induced membrane-bound CD14, TLR4/CD14 complex, and inflammatory cytokines production through β-arrestin-2 in THP-1 cell line

“…Upon agonist binding, β-arrestins1/2 is recruited to the plasma membrane and mediates desensitization and internalization of G-protein-coupled receptor (GPCR) [20] . However, β-arrestins have been considered as novel non-G proteindependent signaling molecules and play functional roles in the regulation of a variety of signaling pathways and in the mediation of cross-talk between receptors [21][22][23] .…”