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Crosstalk between the Glucocorticoid and G Protein‐Coupled Receptor Signaling Pathways Mediated by Arrestins
Author(s) -
Oakley Robert H.,
Cidlowski John A.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb76
Subject(s) - arrestin , microbiology and biotechnology , g protein coupled receptor , signal transduction , glucocorticoid receptor , signal transducing adaptor protein , biology , 5 ht5a receptor , crosstalk , receptor , genetics , physics , optics
The nonvisual arrestins, βarrestin1 and βarrestin2, are multifunctional adaptor proteins that play a central role in G protein‐coupled receptor (GPCR) signaling. Alterations in the cellular complement of arrestins occur in various human diseases and their genetic ablation in mice has severe consequences. Surprisingly, the factors that directly control arrestin gene expression remain unidentified. We now show that glucocorticoids differentially regulate βarrestin1 and βarrestin2 gene expression in human lung adenocarcinoma cells (A549). Glucocorticoids act through the glucocorticoid receptor (GR) to induce the expression of βarrestin1 and repress the expression of βarrestin2. The glucocorticoid‐dependent regulation involves the recruitment of ligand‐activated GR to a conserved and functional glucocorticoid response element (GRE) in intron‐1 of the βarrestin1 gene and to a conserved and functional negative GRE in intron‐11 of the βarrestin2 gene. The marked rise in βarrestin1 following glucocorticoid treatment leads to enhanced activation of the MAP kinase pathway by the protease activated receptor‐1 (PAR1). These studies demonstrate that glucocorticoids can modulate the signaling mode of GPCRs through alterations in arrestin gene expression, revealing a new paradigm for cross‐talk between nuclear and cell surface receptor signaling pathways.