Emerging Evidence on Membrane Estrogen Receptors as Novel Therapeutic Targets for Central Nervous System Pathologies

Nuclear- and membrane-initiated estrogen signaling cooperate to orchestrate the pleiotropic effects of estrogens. Classical estrogen receptors (ERs) act transcriptionally and govern the vast majority of hormonal effects, whereas membrane ERs (mERs) enable acute modulation of estrogenic signaling and have recently been shown to exert strong neuroprotective capacity without the negative side effects associated with nuclear ER activity. In recent years, GPER1 was the most extensively characterized mER. Despite triggering neuroprotective effects, cognitive improvements, and vascular protective effects and maintaining metabolic homeostasis, GPER1 has become the subject of controversy, particularly due to its participation in tumorigenesis. This is why interest has recently turned toward non-GPER-dependent mERs, namely, mER alpha and mER beta. According to available data, non-GPER-dependent mERs elicit protective effects against brain damage, synaptic plasticity impairment, memory and cognitive dysfunctions, metabolic imbalance, and vascular insufficiency. We postulate that these properties are emerging platforms for designing new therapeutics that may be used in the treatment of stroke and neurodegenerative diseases. Since mERs have the ability to interfere with noncoding RNAs and to regulate the translational status of brain tissue by affecting histones, non-GPER-dependent mERs appear to be attractive targets for modern pharmacotherapy for nervous system diseases.

Automated summary

Nuclear- and membrane-initiated estrogen signaling collaborate to regulate the diverse effects of estrogens. Classical estrogen receptors (ERs) control transcriptional activity and most hormonal effects, while membrane ERs (mERs) allow rapid modulation of estrogen signaling and exhibit strong neuroprotective capacity without nuclear ER-related side effects. The extensively studied mER, GPER1, has shown neuroprotection, cognitive improvement, metabolic homeostasis, and vascular protection, but controversy exists due to its involvement in tumorigenesis. Hence, non-GPER-dependent mERs, such as mER alpha and mER beta, have gained attention. These mERs have been found to offer protective effects against brain damage, synaptic plasticity impairment, memory and cognitive dysfunctions, metabolic imbalance, and vascular insufficiency. This suggests their potential as therapeutic targets for stroke and neurodegenerative diseases, as they can influence noncoding RNAs and regulate translational status in brain tissue by affecting histones.