NMDA receptor type 2D gene as target for estrogen receptor in the brain

Although it is well known that estrogen exerts its effect in the brain, the direct target genes transcriptionally regulated by estrogen or rather estrogen receptor (ER) are almost unknown. During the search for estrogen receptor-binding sites from human CpG island library, we found one genomic DNA fragment corresponding to the putative 3'-untranslated region of human NMDA receptor subunit 2D (NR2D) gene. It contained at least four half palindromic estrogen responsive elements (hEREs) within two hundred nucleotides, which was conserved also in the rat. Interestingly, the NR2D mRNA is co-localized with ERalpha and/or ERbeta mRNA in a number of regions of rat brain. We have also demonstrated that NR2D mRNA is up-regulated in rat hypothalamus by estrogen possibly via hEREs identified here. Thus, we suggest that NR2D is one of the direct targets of estrogen receptors which are involved in reproductive as well as non-reproductive actions in the brain.