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Gene & Protein in Disease GPER1 in brain and heart diseases

direct impact of EGCG for schizophrenia treatment was neuronal damage in the hippocampus after status
disproved in a clinical trial conducted by Loftis et al. epilepticus. Furthermore, a relationship between GPER1
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In a ketamine-induced rat model of schizophrenia, the KD and increased neuronal inflammation was established
administration of GEN reduced schizophrenia-related based on increased microglial activation and elevated
symptoms in male rats in combination with standard secretion of inflammatory factors in the hippocampus post
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clozapine treatment. However, the researchers did not status epilepticus (section 2.1). Zhang et al. used a similar
indicate a direct relationship to the activation of GPER1 lithium chloride- and pilocarpine-based epilepsy model to
by GEN. To summarize the results from recent studies, explore temporal lobe epilepsy in male Sprague–Dawley
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GPER1 plays a key role in the pathology of schizophrenia rats, showing improvement in learning and memory
because its lower expression levels in certain brain regions abilities after GPER1 activation as well as assuming a role
were correlated with this disease. Hence, GPER1 expression of GPER1 in synaptic plasticity. Nevertheless, there are
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is correlated with schizophrenia symptoms (Figure 1) also contradictory results from Kurt et al. who reported
and should be further investigated for novel therapeutic increased development of pentylenetetrazole-induced
approaches. Moreover, the effect of GPER1 activation by epileptic seizures after injections with E2 or the GPER1
estrogen or synthetic agonists has to be clarified in clinical agonist G-1. However, the antagonist G-15 exerted no
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studies. effect on seizures. Consistent with the results of Zuo
et al. and Zhang et al., Wang et al. analyzed human
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2.5. Epilepsy patient-derived material and showed that a decrease
Sex-specific differences in epilepsy are well documented, in GPER1 mRNA and GPER1 protein levels negatively
although the alignment varies depending on the subtype correlated with seizure frequency in female but not in
of epilepsy. A higher prevalence of localization-related male patients with focal cortical dysplasia IIb (FCDIIb)
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symptomatic epilepsy has been reported in men; however, and tuberous sclerosis complex (TSC), both of which
women are more often affected by idiopathic generalized are groups of malformations in cortical development
epilepsy. The molecular mechanisms behind this and associated with epilepsy. Interestingly, the authors
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discrepancy remains to be clarified. In general, epilepsy is a also confirmed a significant reduction in GPER1 protein
chronic neurological disorder accompanied with repeated levels in the microglia of female patients with FCDIIb and
seizures involving hyperexcitability of the neuronal TSC, as well as elevated NF-κB-mediated inflammatory
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network based on impaired neuronal functions. Although signaling. Remarkably, in vitro experiments revealed
various mechanisms are discussed as molecular reasons reduced NF-κB protein and neuronal excitability by the
for sex-specific differences in epilepsy, the involvement of altered frequency of spontaneous excitatory postsynaptic
steroids in the regulation of hyperexcitability is one of the currents under the application of the GPER1 agonist G-1.
most investigated connections. The first studies of the The authors, thus, concluded that GPER1 might exert an
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mid-20 century implied a relationship between the sex antiepileptogenic effect in female patients with FCDIIb
th
hormone E2 and seizures in women with epilepsy; 143,144 and TSC. 149
however, currently, there is substantial evidence that During the past few decades, the impact of nutrition,
GPER1 as a receptor might play a role in this axis. In a diet schemes, and certain secondary plant metabolites
case report of a male child suffering from intellectual has emerged in terms of supportive therapy options
disability featuring autistic behavior and epilepsy, there for epilepsy. 150-153 Consistent with this, secondary plant
was an unbalanced translocation involving a co-occurrent metabolites such as EGCG and GEN, which exert a
microdeletion in the chromosomal region 7p22.3 that also regulatory effect on GPER1 expression, 76,154 have also been
affects GPER1. Two independent studies using rodent discussed as promising candidates for additive nutrition
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epilepsy models disclosed a protective role of GPER1 by in terms of epilepsy seizure prevention or attenuation.
reducing seizure severity and improving learning and Nonetheless, there are no data on the direct interaction of
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memory abilities as well as diminishing hippocampal these molecules with GPER1 or epigenetic modifications
neuron damage in epileptic rats. In particular, Zuo et al. in epilepsy pathology or treatment. Altogether, these
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used lithium chloride- and pilocarpine-induced epileptic different data sets strongly suggest the involvement of
male rats, which were genetically modified by the RNA- GPER1 in the pathophysiology of epilepsy, particularly
guided clustered regularly interspaced short palindromic with regard to a potential role in the molecular
repeats (CRISPR)-Cas9 nuclease technology to receive mechanism underlying sex-specific differences. However,
a GPER1 KD for further experiments. Using this model, the exact underlying mechanism has to be clarified due to
they demonstrated an increase in seizure severity in the the controversial results regarding the role of GPER1 in
epileptic rats with the GPER1 KD, as well as intensified epilepsy (Figure 1).

Volume 4 Issue 1 (2025) 9 doi: 10.36922/gpd.4632