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Gene & Protein in Disease GPER1 in brain and heart diseases

Despite the impact of GPER1 on MDD itself, Lei et al. that were exposed to polycytidylic acid (a viral mimetic)
focused on the effects of low concentrations of fluoxetine or saline. N-acetylcysteine (NAC) has been evaluated
(an antidepressant drug) resulting in the upregulation of in schizophrenia due to the involvement of glutathione
ERα expression, which consequently mimics estrogen-like mechanisms in its neurobiology to prevent schizophrenic
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effects. In contrast, in vitro studies have demonstrated symptoms, which were assessed by behavioral and
that fluoxetine upregulates the expression of E2 and oxidative alterations in the prefrontal cortex and striatum
downregulates the expression of ERα and ERβ. 119,120 as well as GPER1 expression. In particular, in female
Koitmäe et al. investigated the modulation and sex-specific rats, there was an increase in the expression of GPER1,
functionality of GPER1 in the hippocampal network in α7-nicotinic acetylcholine receptor, and parvalbumin in
a GPER1 KO mouse model using both male and female interneurons, which may contribute to a better response
mice. GPER1 modulation resulted in reduced neuronal of female rats to NAC. These results emphasize the impact
excitability, which may induce sex-specific cognitive of sex-specific differences in the preventive effects of NAC
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deficits or sex-specific differences in mood disorders. in a rat two-hit schizophrenia model. Peripheral blood
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Over the past few decades, the relationship of depression, mononuclear cells obtained from male and female patients
anxiety, and mood disorders with certain diets or with schizophrenia were converted into microglia-like
supplementary nutrients has been widely discussed. 122-124 cells to measure GPER1 expression levels. Furthermore,
In particular, nutrients such as N-oleyl-ethanolamine and an elevated expression of GPER1 was detected in the
EGCG reportedly attenuate insulin resistance, depression, hippocampal region of a two-hit female mouse model
and eating disorders. In this context, the N-methyl-d- in the proestrus phase. In contrast, two-hit male mouse
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aspartate receptor (NMDAR) pathway has been shown to be models with deficient prepulse inhibition of the startle
activated by the intake of EGCG-rich food, with beneficial reflex exhibited an overall lower hippocampal mRNA
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effects on cognition and hippocampal serotonin levels expression of GPER1. A study comprising 90 patients
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in a rat chronic mild stress model. Besides the extensive with schizophrenia, including 64 patients with treatment-
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literature on the impact of nutrients on mood disorders, resistant schizophrenia (TRS; 45.3% males and 54.7%
there are no data on the direct impact of nutrients on females) and 26 with partially responsive schizophrenia
GPER1. Based on GPER1 activation by EGCG in terms (PRS; 46.2% males and 53.8% females), investigated
of neuroinflammation (section 2.1), a putative role in potential sex differences in the association between TRS
the development of mood disorders could be assumed. and IL-6 levels.
Current research in treating depression focuses on single The study by He et al. indicated that patients with TRS
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pathways and/or single target receptors. Nonetheless, the had higher serum IL-6 levels than those with PRS. In female
pathogenesis of depression is a complex combination of patients, IL-6 levels were significantly higher in the TRS
various signaling molecules and targets. Alterations in cohort than in the PRS cohort, indicating a possible link
estrogen levels can cause symptoms of depression, and between the inflammatory response system and severity
stabilization of estrogen levels could alleviate the disease of schizophrenia. This link may play a pivotal role in the
outcome involving GPER1 signaling (Figure 1). pathogenesis of TRS in a sex-specific manner. Another
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study by Zhang et al. investigated schizophrenia induced
2.4. Schizophrenia
by the administration of dizocilpine (MK-801), a non-
Since the initial studies on sex-specific effects on the competitive NMDAR antagonist, in GPER1 KO and WT
development of schizophrenia by Kraepelin in 1919, mice. Subsequently, the effects on learning, memory, and
accumulated evidence has shown that sex-specific social interaction as well as the protein expression levels
differences influence the epidemiology, symptomatic of the NMDAR NR2B (NR2B)/calmodulin-dependent
expression, life course, and response to antipsychotics in protein kinase II (CaMKII)/CREB signaling pathway were
individuals with schizophrenia. 128,129 In a study involving analyzed. Treatment of GPER1 KO mice with MK-801
36 individuals with schizophrenia and 30 age- and sex- resulted in significant impairment of memory and long-
matched healthy control participants, male patients with term learning compared with that in the treated WT mice.
schizophrenia showed higher serum GPER1 levels than Furthermore, in GPER1 KO mice, the expression levels
healthy male controls, but there was no difference in GPER1 of proteins related to the NR2B/CaMKII/CREB signaling
serum levels between schizophrenia-affected and healthy pathway were downregulated after MK-801 treatment,
women (Table 1). In 2020, a two-hit animal model of showing that GPER1 is an important player in cognitive,
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the uprising symptoms of schizophrenia combining learning, and memory functions. Recent studies have
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exposure to perinatal infection (first-hit) with peripubertal investigated the effect of certain nutrients and natural
unpredictable stress (second-hit) was investigated in rats molecules through various research approaches. 135,136 The

Volume 4 Issue 1 (2025) 8 doi: 10.36922/gpd.4632