Beta(2)-adrenergic receptors potentiate glucocorticoid receptor transactivation via G protein beta gamma-subunits and the phosphoinositide 3-kinase pathway.
Glucocorticoid hormones influence manifold neuronal processes including learning, memory, and emotion via the glucocorticoid receptor (GR). Catecholamines further modulate these functions, although the underlying molecular mechanisms are poorly understood. Here, we show that epinephrine and norepinephrine potentiate ligand-dependent GR transactivation in a hippocampal cell line (HT22) via beta(2)-adrenergic receptors. This enhancement was strongest at low concentrations of glucocorticoids and was accompanied by increased GR binding to a glucocorticoid-responsive element (GRE). beta(2)-Adrenergic receptor-mediated GR enhancement was relayed via G protein beta gamma-subunits, insensitive to pertussis toxin and independent of protein kinase A (PKA). In contrast, the catecholamine-evoked GR enhancement was strongly reduced by wortmannin, suggesting a critical role for phosphoinositide 3-kinase (PI3-K). In agreement, epinephrine directly activated PI3-K in vivo. Similarly, stimulation of tyrosine kinase receptors coupled to PI3-K activation, e.g. receptors for insulin-like growth factor I (IGF-I) or fibroblast growth factor (FGF), increased GR transactivation. Further analysis indicated that G protein-coupled receptor (GPCR) and tyrosine kinase receptor signals converge on PI3-K through separate mechanisms. Blockade of GR enhancement by wortmannin was partially overcome by expression of the downstream-acting protein kinase B (PKB/Akt). Collectively, our findings demonstrate that GPCRs can regulate GR transactivation by stimulating PI3-K. This novel cross-talk may provide new insights into the molecular processes of learning and memory and the treatment of stress-related disorders.
Max Planck Institute of Psychiatry, D-80804 Munich, Germany.
P
P
Schmidt
F
F
Holsboer
D
D
Spengler
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000187:drug effects / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D015533:Transcriptional Activation; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D002867:Chromones; D017868:Cyclic AMP-Dependent Protein Kinases; D003907:Dexamethasone; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D020962:Heterotrimeric GTP-Binding Proteins; D006727:Hormone Antagonists; D007334:Insulin-Like Growth Factor I; D015735:Mifepristone; D009025:Morpholines; D009638:Norepinephrine; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017526:Receptor, IGF Type 1; D018343:Receptors, Adrenergic, beta-2; D017468:Receptors, Fibroblast Growth Factor; D011965:Receptors, Glucocorticoid; D010566:Virulence Factors, Bordetella; C118981:G-protein Beta gamma; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one