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Gene & Protein in Disease GPER1 in brain and heart diseases

2.6. Autism spectrum disorders (ASDs) and established a highly sensitive and specific ASD prediction
attention-deficit/hyperactivity disorder (ADHD) model, suggesting GPER1 as a prognostic factor (Table 1)
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Next to the previously described neurological disorders, and underscoring its protective role in ASD (Figure 1).
a sexually dimorphic prevalence is also present in ASDs, ASD and ADHD often co-occur and share characteristics
as approximately four-fold more males are affected than and overlapping traits. Although ADHD represents one of
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females. Regarding the involvement of GPER1, a the most frequent neuropsychiatric disorders in children,
previous study reported a significant negative correlation data from the ADHD Observational Research in Europe
between GPER1 serum levels and ASD. They analyzed 45 clearly revealed a higher prevalence of ADHD in boys than
children aged 3 – 12 years and 40 age- and sex-matched in girls, with the ratio varying by country, ranging from
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controls and found lower serum levels of GPER1 in patients 3:1 to 16:1. Based on the general known neuroprotective
with ASD than in healthy controls. However, the study role of GPER1 and the association of its downregulation
showed no correlation between GPER1 serum level and in other neurodevelopmental disorders such as ASD and
E2 level nor between age in male or female young patients schizophrenia, researchers also investigated the blood
(Table 1). Furthermore, a case report described a male serum levels of E2 and GPER1 in children with ADHD and
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patient suffering from neurodevelopmental abnormalities age- and sex-matched controls. Interestingly, children with
with autistic features and epilepsy, who harbored a ADHD showed significantly reduced GPER1 serum levels,
translocation involving a co-occurrent microdeletion on but their E2 levels remained unaltered. Furthermore, there
chromosomal region 7p22.3 also affecting GPER1, further were no significant differences in GPER1 or E2 levels
suggesting that GPER1 plays a role in ASD. Another between male and female patients with ADHD or between
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study explored the effect of GPER1 in a valproic acid- ADHD subgroups (Table 1). Similarly, a study from
induced rat model of ASD, where the researchers analyzed China investigated the role of a GPER1 polymorphism
the effect of the intraperitoneal application of the GPER1 in the social function of 135 children with ADHD. No
agonist G-1 in male rats in two different doses for 21 days. significant difference was detected in the genotypic
They observed G-1-induced decrease in hyperactivity, frequencies of the c.-9T/C and c.789G/A loci between
anxiety, social preferences, declined spatial memory, male and female children. However, higher school scores
and repetitive behavior in the male ASD rats. In terms and improved learning were significantly associated with a
of molecular biological changes, there was an increase in TC genotype for the c.-9T to C locus compared with that in
neurotransmission and depletion in oxidative stress in the children with a TT genotype. This study further suggested
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hippocampus, as well as a reduced mRNA expression level an important role of GPER1 in the ADHD phenotype
of IL-1b but an increase in the expression of GPER1, retinoic (Figure 1). Nonetheless, neither the epigenetic regulation
acid-related orphan receptor-a (RORa), and aromatase in of GPER1 nor the impact of nutraceuticals on GPER1 has
the hippocampus after G-1 treatment. This result strongly been reported in the context of ASD or ADHD to date.
suggests a significant role of GPER1 in the sex-specific 2.7. Migraine and pain
prevalence of ASD, and G-1 treatment appears to be a
promising therapeutic approach. Consistent with the Based on the pioneering work of Berkley, researchers
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results of Hameed et al., another study again emphasized have intensively examined sex-specific differences in
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the important role of GPER1 in ASD and developed a pain-associated diseases over decades. At present, it
prediction model for ASD development based on GPER1 is well-known that several pain conditions, such as
expression among four other genes. The authors conducted migraine, fibromyalgia, and temporomandibular disorder,
a longitudinal follow-up study of 2623 newborns over are more prevalent in women than in men. However, there
3 years and evaluated the transcript levels of superoxide are certain painful syndromes that affect men more than
dismutase-2 (SOD2), RORa, progesterone receptor, and women, such as cluster headache. 163-165 The major origin
GPER1, as well as two epigenetic markers at the RORa for these sex-specific differences in pain are probably
promoter and oxidative stress markers in umbilical cord hormonal factors, 166,167 because the prevalence of migraine,
blood mononuclear cell specimen. Their observations for instance, significantly decreases at menopause, thus
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identified 41 children with ASD, who had significantly suggesting a role of hormonal receptors (e.g., GPER1) in
higher levels of oxidative stress as well as H3K9me3 histone the context of sex-specific differences in pain. GPER1 can
modifications at the RORa promoter than healthy children. mediate post-operative hyperalgesia in dorsal root ganglia
Moreover, children with ASD suffered from diminished neurons in the rostral ventromedial medulla, which
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gene expression levels of SOD2, RORa, and GPER1, whereas contributes to the chronification of post-operative pain;
their progesterone receptor expression levels were higher. orofacial inflammatory pain by microglia in the rostral
Using this specific gene expression pattern, the authors ventral medulla; and continuous neuronal sensitization
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Volume 4 Issue 1 (2025) 10 doi: 10.36922/gpd.4632