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Gene & Protein in Disease GPER1 in brain and heart diseases

cellular functions primarily at the transcriptional level, (CDK) 6 and cyclin E1/CDK2. Furthermore, protein
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the novel G protein-coupled ER 1 (GPER1, GPR30), a kinases such as protein kinase C (PKC) and PKA can be
member of the seven-transmembrane G protein-coupled activated by intracellular calcium, which acts as a second
receptor family, is capable of transmitting rapid signaling messenger to activate downstream effector proteins
transduction through G proteins. GPER1 binds to through phosphorylation. A previous study detected
17β-estradiol (E2) with high affinity, mediating rapid GPER1-mediated estrogen signaling in neuroblastoma
estrogen-dependent cellular signaling responses through SH-SY5Y cells, in which GPER1 activation is followed by
second messengers such as cyclic adenosine rapid calcium mobilization and PKC activation; hence,
monophosphate (cAMP) and calcium as well as harboring these pathways play a key role in neurological signaling.
the additional ability to affect gene expression. 8-10 GPER1 is Moreover, GPER1 mediates calcium signaling at the
generally localized in the plasma membrane and transcriptional level during several processes, such as
intracellularly in the endoplasmic reticulum as well as regulation of opioid-dependent signaling in the brain.
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early endosomes, but it is absent in the nucleus of human Similarly, estrogen uncouples other G -GPCRs such as
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embryonic kidney 293 (HEK293) cells. In general, the gamma-aminobutyric acid B and opioid receptor-like-1 by
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subcellular localization of GPER1 differs among various activating G protein-coupled inwardly rectifying potassium
cell types, tissues, age, sex, and species. In particular, channels. This activation is also dependent on the activation
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GPER1 is reportedly located in the plasma membrane of of phospholipase C, PKA, and PKC. Regarding the
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breast cancer cells lacking ERα and ERβ (SKBR3) and the interactome of GPER, a study by Ahmadian Elmi et al.
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inner membrane of the endoplasmic reticulum in monkey reported 73 potential GPER1 interactions, including a
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kidney fibroblasts. In rat oxytocin neurons, GPER1 was direct interaction of GPER1 with CLPTM1, regulator of
expressed primarily in the Golgi but was absent in the GABA type A receptor forward trafficking, and an indirect
plasma membrane. In a study comprising male and interaction of GPER1 with regulatory beta and catalytic
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female rats, GPER1 expression was detected in all neurons alpha subunits of glucosidase II, both of which associate
located in the trigeminal ganglion on the cell surface and with CLPTM1 regulator of GABA type A receptor forward
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in the cytoplasm. However, in the cardiomyocytes of trafficking. They showed that the overexpression of stromal
female rats, GPER1 expression was enhanced in the interaction molecule 1 and additional depletion of calcium
perinuclear region. Live cell imaging of mouse myoblast stores affected GPER1 maturation, trafficking, and calcium
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C2C12 cells, Madin–Darby canine kidney epithelial cells, signaling, with GPER1 becoming more nuclear.
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and human ductal breast epithelial tumor T47-D cells Furthermore, GPER1 signaling may be dependent on
revealed that even after reaching the plasma membrane, complex formation with other receptors such as the
GPER1 was detectable in distinct puncta, indicating that β1-adrenergic receptor, a membrane-associated guanylate
the receptor undergoes constitutive endocytosis, kinase scaffold protein, and PKA-anchoring protein.
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highlighting its dynamic processing. 16,17 The first step in Moreover, GPER1 increases the expression of the hypoxia-
GPER1-mediated rapid signaling is the activation of G inducible factor 1 subunit alpha-dependent vascular
proteins with subsequent activation of different endothelial growth factor that enhances angiogenesis and
downstream signaling pathways; GPER1 increases progression in breast cancer. At present, GPER1 is widely
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estrogen-dependent extracellular signal-regulated kinase discussed as an important receptor mediating sex-specific
1/2 (ERK1/2) activity through G -mediated activation or differences in both health and disease, including the CNS
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G -mediated transactivation of adenylyl cyclase and and cardiovascular system. Besides ERα and ERβ, GPER1
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s
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epidermal growth factor receptor (EGFR). Regarding the is widely expressed in the excitable tissue of the brain, that
GPER1-dependent signaling cascades of non-genomic is, in various regions of the nervous system, including the
effects, the activation of GPER1 by E2 causes an increase in hypothalamus, hippocampus, cerebral cortex, dorsal horn
intracellular calcium levels, likely due to the release of of the spinal cord, and primary afferent neurons,
stored calcium rather than the entry of calcium from the emphasizing its emerging role in neurological diseases. 20,28-32
extracellular space. The concentration of intracellular GPER1 is also expressed in the excitable tissue of the heart,
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cAMP and phosphorylation of cAMP response element- that is, the arterial wall, where its deletion causes left
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binding protein (CREB) increased on the binding of the ventricular dysfunction and adverse remodeling, which
specific GPER1 agonist G-1 to GPER1. Consequently, the was analyzed using sex-specific gene profiling. Notably,
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activation of GPER1 by G-1 facilitated cell proliferation E2 has previously been associated with sex-specific
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through the cAMP/protein kinase A (PKA)/p-CREB differences in hypertension, 35,36 hypertrophy, heart
pathway and subsequently upregulated the levels of cell failure, and cardiac stress, 39,40 indicating that ERs play a
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cycle regulators such as cyclin D1/cyclin-dependent kinase crucial role in the development of cardiovascular diseases.
Volume 4 Issue 1 (2025) 2 doi: 10.36922/gpd.4632