Differential regulation of estrogen receptor alpha, glucocorticoid receptor and retinoic acid receptor alpha transcriptional activity by melatonin is mediated via different G proteins

Melatonin has been shown to bind to the MT1 G protein-coupled receptor (GPCR) in MCF-7 breast cancer cells to modulate the estrogen response pathway suppressing estrogen-induced estrogen receptor alpha (ER alpha) transcriptional activity, blunting ER/DNA binding activity and suppressing cell proliferation. In these studies we have examined the effect of melatonin on the transcriptional activity of the ER alpha and other members of the steroid/thyroid hormone receptor superfamily, namely, the glucocorticoid receptor (GR) and the retinoic acid receptor alpha (RAR alpha). As with the ER alpha, melatonin represses ligand (dexamethasone)-induced activation of the GR. This effect of melatonin on ER alpha and GR is blocked by pertussis toxin (PTX) suggesting that melatonin's actions may be mediated via a PTX-sensitive G(alpha i) protein. In contrast, melatonin potentiates the action of all-trans-retinoic acid on RAR alpha transcriptional activation and enhances RAR alpha/DNA binding activity, an action which is not PTX-sensitive. Expression of a dominant-positive G(alpha i2) protein, with which the MT1 receptor has been shown to couple, is able to mimic the effect of melatonin on ER alpha but not RAR alpha transcriptional activation in breast cancer cells. This demonstrates that GPCRs can modulate the transcriptional activity of various steroid receptors in response to their ligand through activation of different G protein signaling pathways.