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

Wnuk, Agnieszka; Przepiórska, Karolina; Pietrzak, Bernadeta Angelika; Kajta, Małgorzata

doi:10.3390/ijms24044043

Cited by 17 publications

(18 citation statements)

References 159 publications

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“…Although the link between rapid E2 signaling and behavioral control has not previously been described in gonadally intact female rodents, there is a rich literature detailing signaling mechanisms of membraneassociated ER signaling [87][88][89][90] . Here, we find that rapid E2 signaling at membrane-associated receptors promotes synaptic excitation of BNST CRF neurons that are required for motivated alcohol drinking and more engaged when females are in a high ovarian E2 state.…”

Section: Discussionmentioning

confidence: 99%

Rapid nongenomic estrogen signaling controls alcohol drinking behavior

Zallar,

Rivera-Irizarry,

Hamor

et al. 2023

Preprint

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The overconsumption of alcohol contributes to a multitude of negative health outcomes, especially in women, who are more susceptible to its effects and more likely to develop alcohol dependence than men with the same early history of alcohol consumption. Binge alcohol drinking is prominent during reproductive years and correlated with high circulating estrogen in women, and rodent studies show that female rodents with intact ovaries consume more alcohol than males. However, the causal role of ovarian E2 in intact animals in alcohol drinking has not been established. Here, we show that intact female mice consume more alcohol and display reduced avoidance behavior when they have elevated levels of circulating E2 during proestrus compared to other estrous cycle stages in individual mice. We found that high ovarian E2 promotes alcohol drinking in females, but not anxiolysis, through rapid nongenomic E2 signaling at ERα in the bed nucleus of the stria terminalis (BNST). Acute administration of intra-BNST E2 in low ovarian E2 mice enhanced binge alcohol intake, while acute systemic inhibition of E2 synthesis and acute blockade of ERα signaling in the BNST reversed the pro-drinking effects of high ovarian E2 status. In contrast, acute E2 manipulations were unable to alter the effects of ovarian E2 status on avoidance behavior, suggesting genomic mechanisms are required for the anxiolytic effects of ovarian E2. We further show that corticotropin-releasing factor (CRF) neurons in the BNST are an important mediator of these effects of rapid E2 signaling, as high E2 rapidly enhanced synaptic excitation of BNSTCRFneurons and promoted their pro-alcohol drinking behavioral role. Thus, we uncover a mechanism by which ovarian hormones in intact female mice control alcohol drinking behavior, and we provide the first mechanism by which ovarian E2 control of behavior is mediated by a rapid, nongenomic signaling mechanism.

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Section: Discussionmentioning

confidence: 99%

Rapid nongenomic estrogen signaling controls alcohol drinking behavior

Zallar,

Rivera-Irizarry,

Hamor

et al. 2023

Preprint

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“…Estrogen receptors (ER) are located in the nucleus and consist of two types of classical nuclear receptors, ERα and ERβ, which mediate the effects of estrogen 204,205 . Studies have shown that ER is closely related to the occurrence and development of breast cancer, in which the overexpression of ER α (ER‐positive) accounts for 70% of breast cancer, 206 thus being a well‐established target for the treatment of breast cancer 207 .…”

Section: Vhl Ligands and Their Utilizations In Protacs For Cancer Dru...mentioning

confidence: 99%

“…Estrogen receptors (ER) are located in the nucleus and consist of two types of classical nuclear receptors, ERα and ERβ, which mediate the effects of estrogen. 204 , 205 Studies have shown that ER is closely related to the occurrence and development of breast cancer, in which the overexpression of ER α (ER‐positive) accounts for 70% of breast cancer, 206 thus being a well‐established target for the treatment of breast cancer. 207 Currently approved endocrine treatments for breast cancer include aromatase inhibitors (AIs), like letrozole, selective ER modulators (SERMs), like tamoxifen, and selective ER degraders (SERDs), like fulvestrant.…”

Section: Vhl Ligands and Their Utilizations In Protacs For Cancer Dru...mentioning

confidence: 99%

PROTACs: A novel strategy for cancer drug discovery and development

Han

Sun

2023

MedComm

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Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: a small molecule that binds to a target protein, an E3 ligase ligand (consisting of an E3 ligase and its small molecule recruiter), and a chemical linker that hooks first two components together. In the past 20 years, we have witnessed advancement of multiple PRO-TAC degraders into the clinical trials for anticancer therapies. However, one of the major challenges of PROTAC technology is that only very limited number of E3 ligase recruiters are currently available as E3 ligand for targeted protein degradation (TPD), although human genome encodes more than 600 E3 ligases. Thus, there is an urgent need to identify additional effective E3 ligase recruiters for TPD applications. In this review, we summarized the existing RING-type E3 ubiquitin ligase and their small molecule recruiters that act as effective E3 ligands of PRO-TAC degraders and their application in anticancer drug discovery. We believe that this review could serve as a reference in future development of efficient E3 ligands of PROTAC technology for cancer drug discovery and development.

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“…Accordingly, estradiol treatment of women that were exposed to interpersonal violence has been shown to attenuate negative effect of severe PTSD symptoms on fear habituation [e.g., 381 ]. Moreover, mERs are considered a novel treatment target for age-associated memory decline, stroke, and neurodegenerative diseases [e.g., 382 , 383 ].…”

Section: Sex Hormone Co-signalingmentioning

confidence: 99%

Stress-related cellular pathophysiology as a crosstalk risk factor for neurocognitive and psychiatric disorders

Palamarchuk,

Slavich,

Vaillancourt

et al. 2023

BMC Neurosci

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In this narrative review, we examine biological processes linking psychological stress and cognition, with a focus on how psychological stress can activate multiple neurobiological mechanisms that drive cognitive decline and behavioral change. First, we describe the general neurobiology of the stress response to define neurocognitive stress reactivity. Second, we review aspects of epigenetic regulation, synaptic transmission, sex hormones, photoperiodic plasticity, and psychoneuroimmunological processes that can contribute to cognitive decline and neuropsychiatric conditions. Third, we explain mechanistic processes linking the stress response and neuropathology. Fourth, we discuss molecular nuances such as an interplay between kinases and proteins, as well as differential role of sex hormones, that can increase vulnerability to cognitive and emotional dysregulation following stress. Finally, we explicate several testable hypotheses for stress, neurocognitive, and neuropsychiatric research. Together, this work highlights how stress processes alter neurophysiology on multiple levels to increase individuals’ risk for neurocognitive and psychiatric disorders, and points toward novel therapeutic targets for mitigating these effects. The resulting models can thus advance dementia and mental health research, and translational neuroscience, with an eye toward clinical application in cognitive and behavioral neurology, and psychiatry.

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

Cited by 17 publications

References 159 publications

Rapid nongenomic estrogen signaling controls alcohol drinking behavior

Rapid nongenomic estrogen signaling controls alcohol drinking behavior

PROTACs: A novel strategy for cancer drug discovery and development

Stress-related cellular pathophysiology as a crosstalk risk factor for neurocognitive and psychiatric disorders

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