Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors

Abstract

G protein-coupled receptors (GPCRs) compose the largest family of cell surface receptors and are the most common target of therapeutic drugs. The nonvisual arrestins, β-arrestin-1 and β-arrestin-2, are multifunctional scaffolding proteins that play critical roles in GPCR signaling. On binding of activated GPCRs at the plasma membrane, β-arrestins terminate G protein-dependent responses (desensitization) and stimulate β-arrestin-dependent signaling pathways. Alterations in the cellular complement of β-arrestin-1 and β-arrestin-2 occur in many human diseases, and their genetic ablation in mice has severe consequences. Surprisingly, however, the factors that control β-arrestin gene expression are poorly understood. We demonstrate that glucocorticoids differentially regulate β-arrestin-1 and β-arrestin-2 gene expression in multiple cell types. Glucocorticoids act via the glucocorticoid receptor (GR) to induce the synthesis of β-arrestin-1 and repress the expression of β-arrestin-2. Glucocorticoid-dependent regulation involves the recruitment of ligand-activated glucocorticoid receptors to conserved and functional glucocorticoid response elements in intron-1 of the β-arrestin-1 gene and intron-11 of the β-arrestin-2 gene. In human lung adenocarcinoma cells, the increased expression of β-arrestin-1 after glucocorticoid treatment impairs G protein-dependent activation of inositol phosphate signaling while enhancing β-arrestin-1-dependent stimulation of the MAPK pathway by protease activated receptor 1. These studies demonstrate that glucocorticoids redirect the signaling profile of GPCRs via alterations in β-arrestin gene expression, revealing a paradigm for cross-talk between nuclear and cell surface receptors and a mechanism by which glucocorticoids alter the clinical efficacy of GPCR-based drugs.

Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly

“…This is probably due to the high homology and similarity (78 and 88%, respectively) in the amino acid sequence shared by the two β-arrestins (31,32). Moreover, this is also confirmed by the observation that a number of studies investigating β-arrestin protein expression report the use of a polyclonal antibody that recognizes both β-arrestin isoforms, displayed in western blot experiments as two adjacent bands with a very similar molecular weight (32,33). However, it is known that the mRNA evaluation may not always resemble the protein quantification of a given molecule.…”

The biology of the glucocorticoid receptor: New signaling mechanisms in health and disease

“…For example, glucocorticoid induction of βarrestin1 and repression of βarrestin2 occur via an intron1 GRE and intron11 nGRE, respectively (31). Both βarrestin isoforms play critical roles in the termination and transduction of GPCR signals.…”

“…Both βarrestin isoforms play critical roles in the termination and transduction of GPCR signals. By altering the ratio of βarrestin1 and βarrestin2, glucocorticoids shift the balance of G protein and βarrestin-dependent signaling responses for a given GPCR (31). This redirection of the GPCR signaling profile may account for the superior clinical efficacy of glucocorticoid/β2 adrenergic receptor (β2AR) agonist combination therapies currently used for treating asthma and COPD.…”

Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells

“…4C), supporting that the suppression is GR-dependent. Binding with negative GR-response elements (nGREs, with core sequence CTCCnnGGAG) mediates the transrepression of targets by GR (17). Detailed analysis of the ATF3 regulatory region revealed a potential nGRE located between Ϫ2300 and Ϫ2310 bp from the transcription start site (Fig.…”