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Gene & Protein in Disease GPER1 in brain and heart diseases

PD. Furthermore, GPER1 activation results in the (DDT; an insecticide) increases the risk of developing
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protection of DA cells through its anti-inflammatory neuropsychiatric disorders, including depression, anxiety,
effect in the context of PD (Figure 1). and somatization. 111,112 p,p'-DDT, a DTT isomer, induced
depressive-like behavior by decreasing the expression
2.3. Depression and mood disorders levels of serotonin 1A receptor and GPER1, as observed
Sex-specific differences with effects on onset, prevalence, in the mouse brain tissue. p,p’-DDT also caused the
and clinical phenotype have been reported in various attenuation of GPER1 expression, which was independent
studies on major depressive disorder (MDD). 104,105 Cross- of sex and age. Consequently, the disruption of GPER1
national and national epidemiological studies have signaling plays a key role in DDT-induced depressive-like
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shown that women are affected twice as much as men by symptoms. A study demonstrated that extracts from the
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MDD, and symptoms during occurrence and progression root bark of Paeonia suffruticosa (paeonol) were capable of
vary between male and female patients. Despite the fact restoring GPER1 expression levels in the prefrontal cortex
that women are more likely to develop depression, men and hippocampus, mimicking the effects of E2. Paeonol
commit suicide 3 times more frequently during depressive also increased the expression levels of the components of
episodes. Current research provides strong evidence for the PI3K/Akt/mammalian target of rapamycin signaling
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sex-specific molecular mechanisms in human depression, pathway in the prefrontal cortex and hippocampus and that
as a genome-wide association study (GWAS) on MDD of brain-derived neurotrophic factor in the hippocampus
reported that the underlying gene pathways of MDD are of OVX female mice. This study indicated that paeonol
highly sex-dependent. Ignoring critical, sex-specific is beneficial for restoring postmenopausal cognitive
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molecular pathways, and targets for the development of impairment, anxiety, and depression. Recent research
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new therapies is associated with the risk of missing new has demonstrated the effect of E2 on ERβ and/or GPER1
treatment strategies and mechanisms underlying MDD in OVX female rats under chronic mild stress through
development. Therefore, research in the field of sex-specific shortened inhibitory avoidance latency tests using specific
differences in MDD is of special interest for developing ERβ or GPER1 agonists. For instance, Tongta et al. showed
novel therapeutic approaches. Patients with MDD show that GABA- and neurosteroid-associated mRNAs related
higher GPER1 serum levels than controls, indicating to anxiety were altered through ERβ, whereas GPER1
GPER1 as a potential biomarker for the presence of MDD. activation exerted no or opposing effects. Consistent
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Accordingly, a positive correlation could be demonstrated with these findings, Kastenberger et al. described GPER1
between GPER1 serum levels and depression scores as an inductor of anxiogenic effects by estrogen in
(Table 1). Moreover, postmenopausal depression, rodents. They revealed that a potential imbalance in the
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caused by a decrease in female sex hormones, was expression of ERβ (anxiolytic) and GPER1 (anxiogenic)
correlated with MDD in OVX female rats. Intracerebral may be responsible for the negative symptoms of estrogen
treatment with the GPER1 agonist G-1 in OVX female replacement therapy in humans. In general, estrogens
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rats exerted antidepressant and anxiolytic effects by have been used for the treatment of perimenopausal and
increasing translocator protein phosphorylation through postmenopausal depression in women, irrespective of
PKA signaling. Exposure to endocrine-disrupting antidepressant drug use, to attenuate uprising symptoms
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chemicals such as dichlorodiphenyltrichloroethane with fluctuating estrogen levels during the estrus cycle.
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Table 1. GPER1 serum levels in several neurological and cardiovascular diseases
Disease Alteration in GPER1 serum level Sex-specific differences References
Depression and Elevated GPER1 serum levels in male and No sex-specific differences detected 109
mood disorders female patients diagnosed with MDD
Schizophrenia Elevated GPER1 serum levels in male No difference in GPER1 serum levels between 130
patients diagnosed with schizophrenia schizophrenia-affected women and healthy women
ASD Reduced GPER1 serum levels in male and No sex-specific differences detected 156
female patients with ASD
ADHD Reduced GPER1 serum levels in male and No sex-specific differences detected 160
female patients with ADHD
Hypertension Reduced GPER1 serum levels in No analysis of male patients 199
postmenopausal women with hypertension
Abbreviations: ADHD: Attention-deficit/hyperactivity disorder; ASD: Autism spectrum disorder; GPER1: G protein-coupled estrogen receptor 1;
MDD: Major depressive disorder.

Volume 4 Issue 1 (2025) 7 doi: 10.36922/gpd.4632