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Review
. 2019;17(5):459-471.
doi: 10.2174/1570159X16666180628165107.

Role of Estradiol in the Expression of Genes Involved in Serotonin Neurotransmission: Implications for Female Depression

Olivia Tania Hernández-Hernández  1 , Lucía Martínez-Mota  2 , José Jaime Herrera-Pérez  2 , Graciela Jiménez-Rubio  2
Affiliations
Review

Role of Estradiol in the Expression of Genes Involved in Serotonin Neurotransmission: Implications for Female Depression

Olivia Tania Hernández-Hernández et al. Curr Neuropharmacol. 2019.

Abstract

Background: In women, changes in estrogen levels may increase the incidence and/or symptomatology of depression and affect the response to antidepressant treatments. Estrogen therapy in females may provide some mood benefits as a single treatment or might augment clinical response to antidepressants that inhibit serotonin reuptake.

Objective: We analyzed the mechanisms of estradiol action involved in the regulation of gene expression that modulates serotonin neurotransmission implicated in depression.

Method: Publications were identified by a literature search on PubMed.

Results: The participation of estradiol in depression may include regulation of the expression of tryptophan hydroxylase-2, monoamine oxidase A and B, serotonin transporter and serotonin-1A receptor. This effect is mediated by estradiol binding to intracellular estrogen receptor that interacts with estrogen response elements in the promoter sequences of tryptophan hydroxylase-2, serotonin transporter and monoamine oxidase-B. In addition to directly binding deoxyribonucleic acid, estrogen receptor can tether to other transcription factors, including activator protein 1, specificity protein 1, CCAAT/enhancer binding protein β and nuclear factor kappa B to regulate gene promoters that lack estrogen response elements, such as monoamine oxidase-A and serotonin 1A receptor.

Conclusion: Estradiol increases tryptophan hydroxylase-2 and serotonin transporter expression and decreases the expression of serotonin 1A receptor and monoamine oxidase A and B through the interaction with its intracellular receptors. The understanding of molecular mechanisms of estradiol regulation on the protein expression that modulates serotonin neurotransmission will be helpful for the development of new and more effective treatment for women with depression.

Keywords: Depression; estradiol; monoamine oxidases; serotonin 1A receptor; serotonin transporter; tryptophan hydroxylase..

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Figures

Fig. (1)
Fig. (1)
Mechanisms of estradiol action. 1) In the classical model of estradiol action, in the absence of ligand, estrogen receptor is associated with heat shock proteins (HSP70 and HSP90). Estradiol interaction induces estrogen receptor conformational changes that allow dissociation of the HSP, promoting dimerization, phosphorylation and high-affinity binding to estrogen response elements (ERE) located within the regulatory regions of target genes. Estrogen receptor modulates target gene transcription by recruiting components of the basal transcriptional machinery (BTM) and by interacting with coregulatory proteins (Coactivators: CoA or Corepressors: CoR). Estrogen receptor can also modulate the expression of genes without directly binding to deoxyribonucleic acid by tethering to other transcription factors through protein-protein interactions in the nucleus, including specificity protein 1 (Sp1) and activator protein 1 (AP-1), nuclear factor kappa B (NF-ҡB) and CCAAT/enhancer binding protein β (C/EBPβ) to regulate gene promoters that lack canonical ERE sequences. 2) Estrogen receptor localized into the cell membrane or cytoplasm has been proposed to mediate estradiol activation of the protein tyrosine Kinase (SrcK)/mitogen-activated protein kinase (MAPK) signaling pathway, and can phosphorylate and active certain nuclear transcription factors. 3) In the non-classical mechanisms of estradiol action, estradiol binding to G protein-coupled estrogen receptor-1 (GPER1) induces cyclic adenosine monophosphate (cAMP) production and MAPK, and activates phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathways.
Fig. (2)
Fig. (2)
Estradiol regulates the expression of tryptophan hydroxylase-2 (TPH-2), monoamine oxidases (MAOs), serotonin transporter (SERT) and serotonin-1A receptor (5-HT1A) through classical mechanisms. Classically, estradiol-activated estrogen receptor dimers contact estrogen response elements (ERE) in the promoter regions of target genes, such as TPH-2, MAO-B and SERT, to initiate transcription. Besides, estrogen receptor can modulate the expression of genes without directly binding to deoxyribonucleic acid by tethering to other transcription factors, including specificity protein 1 (Sp1) and activator protein 1 (AP-1), nuclear factor kappa B (NF-ҡB) and CCAAT/enhancer binding protein β (C/EBPβ). The MAO-A promoter does not contain canonical ERE, however, the presence of three Sp1 sites may provide a mechanism for estradiol regulation. The 5-HT1A gene lacks canonical ERE, but the promoter contains two putative NF-ҡB binding sites that could mediate the estradiol action indirectly through interaction between estrogen receptor and NF-ҡB binding.
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