G protein β interacts with the glucocorticoid receptor and suppresses its transcriptional activity in the nucleus

Extracellular stimuli that activate cell surface receptors modulate glucocorticoid actions via as yet unclear mechanisms. Here, we report that the guanine nucleotide-binding protein (G protein)-coupled receptor-activated WD-repeat G beta interacts with the glucocorticoid receptor (GR), comigrates with it into the nucleus and suppresses GR-induced transactivation of the glucocorticoid-responsive genes. Association of G gamma with G beta is necessary for this action of G beta. Both endogenous and enhanced green fluorescent protein (EGFP)-fused G beta 2 and G gamma 2 proteins were detected in the nucleus at baseline, whereas E a fraction of EGFP-G beta 2 and DsRed2-GR comigrated to the nucleus or the plasma membrane, depending on the exposure of cells to dexamethasone or somatostatin, respectively. G beta 2 was associated with GR/glucocorticoid response elements (GREs) in vivo and suppressed activation function-2-directed transcriptional activity of the GR. We conclude that the G beta gamma complex interacts with the GR and suppresses its transcriptional activity by associating with the transcriptional complex formed on GR-responsive promoters.