Year: 2025
Type: article
Abstract: Background Given the premise that fluctuations in hormone levels affect mood—as seen in conditions like premenstrual dysphoric disorder, perinatal depression, postpartum depression, and premenopausal depression—combined with the observation that major depressive disorder has a lifetime prevalence twice as high in women as in men, our aim was to explore whether antidepressants interact with the biological components of sex steroid receptors, specifically estrogen receptor alpha (ERα), to mediate their therapeutic effects. Aims & Objectives We hypothesized that antidepressants may alter the activity of ERα. Furthermore, we proposed the possibility of a direct interaction with ERα for all antidepressants, with rapid-acting antidepressants preferentially interacting with membrane ERα and initiating non-genomic signaling. Method We utilized various molecular and computational tools (molecular docking and molecular dynamics) to demonstrate that ERα may mediate the effect of antidepressants. To further assess whether rapid-acting antidepressants preferentially affect membrane ERα, distinct genes whose expressions are dependent on the activation of either membrane-initiated or nuclear-initiated ERα signaling (LRRC54 and PgR, respectively) were studied. We also explored the downstream signaling pathways associated with the activation of ERα via western blotting and the possibility of a direct interaction through proximity ligation assay (PLA). Finally, we studied the impact of essential heat-shock proteins in the response evoked by treatment with antidepressants. A one-way ANOVA was used for comparisons between more than two groups, while paired or unpaired Student's t-tests were applied for two-group comparisons. To assess interaction effects, a two-way ANOVA was conducted. Results Our findings suggested that almost all antidepressants are able to directly interact with ERα, in silico in the same pocket site as estradiol. Subsequent in vitro studies revealed that ketamine and imipramine increased the phosphorylation of ERα, an effect mitigated by pretreatment with fulvestrant. Inhibition of the palmitoylation process, through which ERα is localized to the membrane, resulted in reduced receptor activation, supporting the involvement of membrane-bound ERα in the observed molecular impact exerted by antidepressants. Rapid activation of ERα in MCF-7 cells further corroborated the potential involvement of extranuclear ERα that is associated with immediate estrogen signaling. In this regard, ketamine but not imipramine increased the expression of LRRC54 compared to control, which was mitigated after the blockade of ERα. In contrast, imipramine and not ketamine enhanced the expression of PgR, an effect that was abrogated when cells were pretreated with fulvestrant. This distinct profile was also observed in the phosphorylation of key signaling kinases for ketamine and imipramine indicating that the mode of interaction may differ. In situ PLA pointed to close proximity between biotinylated fluoxetine and ketamine and ERα in MCF7 cells, whilst no PLA signal was detected in HEK cells not expressing ERα, demonstrating a potential binding of antidepressants to ERα. Discussion & Conclusions This work emphasizes the role of ERα in mood regulation, identifies ERα as a possible therapeutic target, and raises the possibility that the mechanism of action of all antidepressants may converge on sex steroid receptors. While further studies are warranted, targeting sex steroid receptors could hold promise for the development of novel antidepressant treatments.
Authors: S Arjmand, R Rossi, C Vægter, C Cecchi Kaadt, H Müller, J Sahana, S Sinning, A Landau, G Wegener, S Joca, C Biojone
Institution: Aarhus University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,693
OpenAlex ID: W4413313878