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Gene & Protein in Disease GPER1 in brain and heart diseases

of GPER1 in the colon and brain. More recently, they through G-1 in the dorsal hippocampus was also
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confirmed their results and clarified a key role of GPER1/ shown to regulate memory consolidation, with CREB
AMP-activated protein kinase/sirtuin-1 signaling in phosphorylation playing a role equivalent to that in OVX
the prevention of aging-related neurodegeneration and female mice. Moreover, two recently published reviews
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inflammation induced by indoles from the gut microbiota focused on the effects of estrogen on age-dependent
in male mice. 63 memory loss and AD. 71,72 Nonetheless, only a few studies
Besides its role in the regulation of neuroinflammation, have directly analyzed the GPER1 and AD interaction.
there are a few studies on the involvement of GPER1 in AD generally exerts a massive impact on a large number
neuronal apoptosis, learning, and memory. Researchers of patients worldwide, and its pathology manifests in
have shown that GPER1 activation after subarachnoid brain areas with increased amounts of amyloid beta (Aβ)
hemorrhage, bleeding in the space between the brain protein, neuropil threads, and neurofibrillary tangles. The
and the surrounding membrane, in rats resulted in protective effect of GPER1 on rat neuronal cells against the
less neuronal apoptosis through Src/EGFR/signal Aβ-induced toxicity was mediated on the administration
transducer and activator of transcription 3 signaling, of the GPER1 agonist G-1 by changing the cell oxidative
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improved neurobehavioral performance, and long-term parameters. Consistent with these findings, Deng et al.
neurofunction in male rats, but not in female rats. It demonstrated an oxabicycloheptene sulfonate-induced
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was also shown that GPER1 is crucial in the reduction of protective effect on Aβ-promoted cytotoxicity through
cognitive impairment and neuronal damage in a mouse activation of the GPER1-phosphoinositide 3-kinase
model of vascular dementia. In this study, the ginsenoside (PI3K)-/Akt and ERK pathway in an in vitro rat glial cell
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Rg1 increased the GPER1 expression level and reduced model of AD. Furthermore, the improving effect of G-1 on
neuronal apoptosis and hippocampal neuronal loss in male recognition and memory was confirmed in an AD mouse
mice. Kim et al. also showed the beneficial impact of the model, where G-1 improved novel object recognition as
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GPER1 agonist G-1 with respect to recognition and spatial well as long-term (24 h) recognition memory in female
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memory consolidation in OVX female mice, as well as but not male mice. Meng et al. revealed sex-specific
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increased CA1 dendritic spine density and hippocampal differences in bisphenol A (BPA) sensitivity, as juvenile
memory consolidation similarly in female mice, which was male rats exhibited elevated BPA-induced neurotoxicity
dependent on actin polymerization and c-Jun N-terminal as well as higher impairment of learning and memory
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kinase signaling. Similar results were reported by Wang compared with that in juvenile female rats. Interestingly,
et al., who analyzed the effect of G-1 in OVX female they demonstrated an involvement of GPER1 in this
rats after global cerebral ischemia. They demonstrated context, as low doses of BPA reduced GPER1 protein
a G-1-induced upregulation of neurogenesis in the expression, especially in male rats, with only high doses
hippocampal dentate gyrus and CA1 region, less CA1 affecting the expression of ERα and ERβ. In particular,
neuronal damage, and improved memory function after the use of the GPER1 antagonist G-15 reduced neuronal
28 days. Mechanistically, astrocyte-derived aromatase- morphogenic damage, emphasizing the role of GPER1
brain-derived estrogen signaling was shown to be involved signaling in this process. Similar effects on reduced
in long-term neuroprotection because the usage of an neuronal morphogenetic impairment were detected by
aromatase antagonist eliminated these effects. It was also the application of the phytoestrogen EGCG, a flavanol and
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demonstrated that GPER1 KO in astrocytes but not in the the major component of green tea polyphenols. Moreover,
neurons of female mice caused significant impairment in BPA-treated male rats, in vivo treatment with EGCG
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of learning and memory, which was accompanied with improved their spatial memory ability, probably based
reactive astrocytes releasing proinflammatory cytokines on its antioxidant activity and competitive binding to
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that damage neurons. The cAMP/PKA/CREB signaling GPER1, resulting in depleted binding of E2 or BPA to
was involved in this effect at the molecular level, regulating GPER1. 78,79 This finding was also supported by Moreno-
the beneficial effects of GPER1 on Praja1 (PJA1), a RING Ulloa et al., who reported a comparable binding pattern
ubiquitin ligase, which binds to Serpina3n, indicating between EGCG and GPER1 to that between GPER1 and its
astrocytic neuroinflammation. This mechanism was agonist G-1. Another recent study demonstrated a role of
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also confirmed for female human astrocytes, as GPER1 GPER1 in the beneficial effects of the oral administration
activation resulted in increased expression of PJA1 and of the phytoestrogen secoisolariciresinol diglucoside
activated CREB. Accordingly, the mRNA levels of GPER1 (SDG) in an AD female mouse model. It was found that
and PJA1 decreased in the plasma of postmenopausal mice fed on the SDG diet exhibited accumulation of the
women with an increase in Serpina3n expression. In gut microbial metabolites enterodiol and enterolactone,
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gonadectomized male mice, in vivo GPER1 activation which are structurally similar to E2. Consequently, this led

Volume 4 Issue 1 (2025) 4 doi: 10.36922/gpd.4632