Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors
- 8 October 2012
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (43), 17591-17596
- https://doi.org/10.1073/pnas.1209411109
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.Keywords
This publication has 26 references indexed in Scilit:
- Biochemical Basis of Asthma TherapyPublished by Elsevier BV ,2011
- How Can 1 + 1 = 3? β2-Adrenergic and Glucocorticoid Receptor Agonist Synergism in Obstructive Airway Diseases: Fig. 1.Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2011
- β-arrestin-mediated receptor trafficking and signal transductionTrends in Pharmacological Sciences, 2011
- Cellular Processing of the Glucocorticoid Receptor Gene and Protein: New Mechanisms for Generating Tissue-specific Actions of GlucocorticoidsJournal of Biological Chemistry, 2011
- Therapeutic potential of β-arrestin- and G protein-biased agonistsTrends in Molecular Medicine, 2010
- Teaching old receptors new tricks: biasing seven-transmembrane receptorsNature Reviews Drug Discovery, 2010
- Beyond Desensitization: Physiological Relevance of Arrestin-Dependent SignalingPublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2010
- Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulationGenome Research, 2009
- Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementiaNeurobiology of Aging, 2008
- Determinants of Cell- and Gene-Specific Transcriptional Regulation by the Glucocorticoid ReceptorPLoS Genetics, 2007