G Protein-Coupled Estrogen Receptor: Rapid Effects on Hippocampal-Dependent Spatial Memory and Synaptic Plasticity

Abstract

In the hippocampus, estrogen regulates gene transcription linked to neuronal growth, neuroprotection, and the maintenance of memory function (1-3). The mechanism is likely to involve genomic regulation through classic estrogen receptor (ER) signaling cascades that influence transcription. Estrogens binding to classic nuclear ERs, alpha (ERα) and beta (ERβ), and have pleotropic effects on development, behavior, and neurophysiological functions, including synaptic plasticity and memory consolidation (4-7). In addition to ERα and ERβ, estrogen can also initiate activation of classical second messenger signaling cascades to influence the activity of G-proteins and a host of kinases, resulting in rapid changes in physiology (8-14). These rapid effects of estrogen are commonly mediated by membrane receptors. In the late 90s, multiple laboratories cloned cDNA/gene for an orphan G-protein-coupled receptor with very low homology with other G-protein-coupled receptors and named it G-protein-coupled receptor 30 (GPR30) (15-20). Later in 2007, the International Union of Basic and Clinical Pharmacology designated GPR30 as G protein-coupled estrogen receptor (GPER) (21); GPER is a seven-transmembrane G-protein-coupled receptor, predominantly expressed on the cell membrane (22). Interestingly, GPER is reported to mediate many of the rapid responses of estradiol in the adult brain, and is widely distributed in the mammalian brain including the plasma membrane of hippocampal neurons (23-31). GPER modulates second messenger signaling cascades involving Gα sand Gα i/o-associated increase in cyclic adenosine monophosphate and phosphoinositide 3-kinase or Src protein kinase respectively (32, 33). Activation of GPER is also associated with phospholipase C, and the inositol receptor and ryanodine receptor-mediated increase in intracellular calcium (24, 34). This commentary is concentrated specifically on the possible rapid effects of GPER in hippocampal-dependent spatial memory function and synaptic plasticity.

Differential Effects of the G-Protein-Coupled Estrogen Receptor (GPER) on Rat Embryonic (E18) Hippocampal and Cortical Neurons

“…1-1 ). Based on the selective binding profiles of GPER agonist G-1 and antagonist G-15 (see Materials and Methods) and physiological studies in the field ( McCarthy, 2008 ; de Valdivia et al, 2017 ; Kumar and Foster, 2020 ), we initially tested the effects of G-1 alone at 100 n m and G-15 alone at 10 n m on the growth of cultured hippocampal and cortical neurons compared with neurons cultured in vehicle (0.1% DMSO). Our results showed that in hippocampal neurons G-1 alone significantly ( p < 0.01) increased average neurite outgrowth (μm), while G-15 alone had no effect ( p > 0.05) compared with vehicle (one-way ANOVA, F (2,638) = 18.46, p < 0.01; Vehicle: 52.4 ± 3.1, n = 264 cells; G-1: 78.1± 4.4, n = 180 cells; G15: 45.2 ± 4.1, n = 197 cells).…”

Nk3R blockade has sex-divergent effects on memory in mice

“…Previous experiments have demonstrated that the memory consolidation effects observed after the administration of osanetant are dependent on the sexual maturity of the mouse [ 7 ], either male or female. Interestingly, given the involvement of sex hormones in the regulation of Nk3R activity on memory formation [ 7 ], estrogen GPCR has recently been shown to modulate hippocampal-dependent memory and long-term potentiation [ 45 ]. Although the Nk3R presents a significant number of heterodimers with AR in males and proestrus females, the Nk3R–GPER heterodimer appears quite more abundant than the rest, pointing to a possible explanation for the increased efficacy of Nk3R during high estradiol levels.…”

Hormone therapy for ovarian cancer: Emphasis on mechanisms and applications (Review)

“…On the other hand, non-genomic effects involve the indirect regulation of gene expression through a variety of intracellular signaling events. The G-protein coupled receptor (GPR)30, also known as G-protein coupled ER1, has been extensively investigated as a membrane ER that activates non-genomic estrogen signaling pathways in a variety of tissues (160). ERα is closely associated with endocrine sensitivity in breast cancer and is a significant mediator of the estrogen response in OC (161,162).…”