Modulation of the transcriptional activity of the Glucocorticoid Receptor by β2-Adrenergic Ligands. Role of PKA and ERK.

FERNANDEZ, NATALIA; SHAYO, CARINA; ZAPPIA, DANIEL; MONCZOR, FEDERICO; DAVIO, CARLOS; GRANJA GALEANO, GINA; DÍAZ NEBREDA, ANTONELA; FITZSIMONS CP

Mar del Plata

Congreso; Sociedad Argentina de Investigacion Clinica (SAIC); 2016

Sociedad Argentina de Investigación Clínica

Glucocorticoid effects on memory consolidation after stressful events are mediated by binding and activation of the Glucocorticoid Receptor (GR) and its interaction with the noradrenergic arousal system. β2-adrenergic receptors (β2AR) are membrane receptors that signal independently through both the Gs-AC-cAMP-PKA and ERK pathways, while the GR is classically considered a ligand-activated transcription factor that modulates the transcriptional activation of responsive genes. Here we set to study the modulation of GR transcriptional activity by β2AR ligands that differentially activate PKA or ERK signaling. We show that, in HEK293T cells transfected with β2AR, isoproterenol and clenbuterol behave as full agonists, stimulating both cAMP and ERK pathways, whereas propranolol and carvedilol behave as biased ligands diminishing cAMP concentration and increasing ERK activity. Cotransfection of a luciferase reporter plasmid under the control of a promoter regulated by the GR-responsive promoter (TAT3-Luc) with plasmids coding for GR and β2AR, resulted in inhibition of dexamethasone-induced GR activity by 50% (p