Synergistic activation of the serotonin-1A receptor by nuclear factor-κB and estrogen

Estrogen exerts profound effects on mood and mental state. The ability of estrogen to modulate serotonergic function raises the possibility that it may play a role in the mechanism associated with depression and its treatment. A cellular mechanism for estrogen to influence mood might be through the regulation of genes involved at various levels of the serotonin system. Here we report that estrogen can up-regulate the expression of the serotonin-1A receptor via a new mechanism involving synergistic activation by nuclear factor-κB (NF-κB) with estrogen receptor α. Interestingly, we observed that only estrogen receptor-α, and not -β, was able to mediate this effect of estrogens. The partial antiestrogen, 4-hydroxytamoxifen, had the same effect as estrogen. In addition, mutation analysis showed that both the transactivation function of p65 and activation function 1 of estrogen receptor-α were essential for this synergistic regulation. Therefore, we propose that NF-κB complexes cooperate with estrogen receptor-α to recruit cofactors into the complex and thereby synergistically activate the serotonin-1A receptor promoter through nonclassical estrogen response elements by a mechanism that does not involve direct receptor binding to DNA.