Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors.
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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, ?-arrestin-1 and ?-arrestin-2, are multifunctional scaffolding proteins that play critical roles in GPCR signaling. On binding of activated GPCRs at the plasma membrane, ?-arrestins terminate G protein-dependent responses (desensitization) and stimulate ?-arrestin-dependent signaling pathways. Alterations in the cellular complement of ?-arrestin-1 and ?-arrestin-2 occur in many human diseases, and their genetic ablation in mice has severe consequences. Surprisingly, however, the factors that control ?-arrestin gene expression are poorly understood. We demonstrate that glucocorticoids differentially regulate ?-arrestin-1 and ?-arrestin-2 gene expression in multiple cell types. Glucocorticoids act via the glucocorticoid receptor (GR) to induce the synthesis of ?-arrestin-1 and repress the expression of ?-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 ?-arrestin-1 gene and intron-11 of the ?-arrestin-2 gene. In human lung adenocarcinoma cells, the increased expression of ?-arrestin-1 after glucocorticoid treatment impairs G protein-dependent activation of inositol phosphate signaling while enhancing ?-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 ?-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.
SUBMITTER: Oakley RH
PROVIDER: S-EPMC3491462 | biostudies-literature | 2012 Oct
REPOSITORIES: biostudies-literature
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