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Synergistic Activation of the Serotonin-1A Receptor by Nuclear Factor-B and Estrogen

Hubrecht Laboratory (S.W., B.v.d.B., P.T.v.d.S.) Netherlands Institute for Developmental Biology 3584 CT Utrecht, The Netherlands Departments of Molecular and Integrative Physiology (B.S.K.) University of Illinois Urbana, Illinois 61801-3704

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-B (NF-B) with estrogen receptor . Interestingly, we observed that only estrogen receptor-, and not -ß, 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- were essential for this synergistic regulation. Therefore, we propose that NF-B complexes cooperate with estrogen receptor- 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.

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