Up-regulation of D1A dopamine receptor gene transcription by estrogen

Estrogen exerts complex physiologic effects on brain functions which could partly be mediated through modulation of the dopaminergic system. Transcription control of the human D1A dopamine receptor gene by estrogenic stimulation was studied in the D1A expressing neuroblastoma cell line SK-N-MC. Transient co-transfection of D1A gene promoter-CAT constructs along with expression vectors for steroid hormone receptors indicated that estrogen, but not progesterone or glucocorticoid, receptors up-regulate transcription of this gene by about 1.7-fold. Serial 5' deletion mutants of the D1A gene upstream region localized the estrogen responsive segment between nucleotides -1472 and -1342 relative to the initiator methionine. This region contains a half palindrome (TGACC) for the consensus estrogen responsive element (ERE). Additional co-transfection experiments revealed that estrogen receptors specifically activate the upstream D1A promoter but not the downstream promoter located in the intron of this gene. Consistent with transient co-transfection experiments, 17beta-estradiol treatment of SK-N-MC cells transfected with an estrogen receptor expression vector resulted in an approximately 20% increase in steady-state levels of long D1A transcripts derived from the upstream promoter but not of short transcripts originating from the intron promoter. These observations demonstrate a molecular basis for estrogen induced up-regulation of D1A gene transcription and provide a mechanism for modulation of central dopaminergic functions by this hormone.