Converse regulatory functions of estrogen receptor-α and -β subtypes expressed in hypothalamic gonadotropin-releasing hormone neurons

Estradiol (E-2) acts as a potent feedback molecule between the ovary and hypothalamic GnRH neurons, and exerts both positive and negative regulatory actions on GnRH synthesis and secretion. However, the extent to which these actions are mediated by estrogen receptors (ERs) expressed in GnRH neurons has been controversial. In this study, Single-cell RT-PCR revealed the expression of both ER alpha and ER beta isoforms in cultured fetal and adult rat hypothalamic GnRH neurons. Both ER alpha and ER beta or individual ERs were expressed in 94% of cultured fetal GnRH neurons. In adult female rats at diestrus, 68% of GnRH neurons expressed ERs, followed by 54% in estrus and 19% in proestrus. Expression of individual ERs was found in 24% of adult male GnRH neurons. ER alpha exerted marked G(i)-mediated inhibitory effects on spontaneous action potential (AP) firing, cAMP production, and pulsatile GnRH secretion, indicating its capacity for negative regulation of GnRH neuronal function. In contrast, increased E-2 concentration and ER beta agonists increase the rate of AP firing, GnRH secretion, and cAMP production, consistent with ER beta-dependent positive regulation of GnRH secretion. Consonant with the coupling of ER alpha to pertussis toxin-sensitive G(i/o) proteins, E-2 also activates G protein-activated inwardly rectifying potassium channels, decreasing membrane excitability and slowing the firing of spontaneous APs in hypothalamic GnRH neurons. These findings demonstrate that the dual actions of E-2 on GnRH neuronal membrane excitability, cAMP production, and GnRH secretion are mediated by the dose-dependent activation of ER alpha and ER beta expressed in hypothalamic GnRH neurons.