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

Estrogen exerts profound effects on mood and mental state. The ability of e strogen to modulate serotonergic function raises the possibility that it ma y 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, Her e we report that estrogen can up-regulate the expression of the serotonin-1 A receptor via a new mechanism involving synergistic activation by nuclear factor-kappaB (NF-kappaB) with estrogen receptor alpha, Interestingly, we o bserved that only estrogen receptor-alpha, and not -beta, was able to media te 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 estr ogen receptor-alpha were essential for this synergistic regulation. Therefo re, we propose that NF-kappaB complexes cooperate with estrogen receptor-al pha to recruit cofactors into the complex and thereby synergistically activ ate the serotonin-1A receptor promoter through nonclassical estrogen respon se elements by a mechanism that does not involve direct receptor binding to DNA.