In humans the ER is encoded by the gene
In humans, the ERα is encoded by the gene ESR1, located on chromosome 6, locus 6q25.1 (Gosden, Middleton, & Rout, 1986). In addition to the full-length ERα isoform (66kDa), several shorter isoforms (36kDa, 46kDa) have been identified as a result of the presence of alternate start codons, or as productos of alternative splicing (Fig. 5). Some of these shorter isoforms do not have the NTD and thus lack the AF-1 domain. Therefore, they cannot activate transcription. Instead, they are able to form heterodimers with the full-length ERα and inhibit its ability to control transcriptional. The shorter isoform, ERα-36, lacks both AF-1 and AF-2 transcriptional activation domains, and it has been shown to exert membrane-initiated signaling events upon binding to estradiol, estriol, and estretrol (Gu et al., 2014), as well as to medicate GPER1 responses (Arnal et al., 2017; Romano & Gorelick, 2018).
On the other hand, ERβ is encoded by the ESR2 gene located in chromosome 14 (14q23–24), and has five known isoforms (Enmark et al., 1997) (Fig. 6). The main difference between the full-length ERβ and the shorter ERβ isoforms is on the C-terminal LBD. Therefore, ERβ isoforms that have no transcriptional activity can also suppress ERα signaling by dimerizing with ERα (Vrtačnik, Ostanek, Mencej-Bedrač, & Marc, 2014).
Finally, the gene coding for the membrane receptor GPER1 is located in chromosome 7 (locus 7p22.3). In terms of structure, GPER1 does not share similarities with ERα or ERβ. As a typical G protein coupled receptor, its structure consists of 7 transmembrane α-helical regions, 4 extracellular segments, and 4 cytosolic segments (Barton et al., 2018). This receptor has low binding affinity (17B-estradiol) when compared to other estrogen receptors (Prossnitz & Barton, 2014). However, this may be important as GPER1 is accountable for rapid responses to estrogen, and activation of intracellular signaling cascades mediated by second messengers (Filardo & Thomas, 2012).
Mechanims of estrogen receptor signaling As a steroid hormone, estrogen can enter the plasma membrane and interact with intracellular ERα and ERβ to exert direct effects by binding to DNA sequences. Alternatively, estrogen can activate intracellular signaling cascades via interaction with the GPER1 and/or ERα and ERβ. Due to differences in the cellular and molecular events leading to gene expression regulation in which estrogen-receptor complexes can either bind directly or indirectly to DNA, estrogen-mediated signaling events ca be divided into genomic and non-genomic. Genomic effects are those involving migration of the estrogen-receptor complexes to the cell nucleus, and direct interaction with beta lactamase inhibitor at specific DNA sequences known as estrogen response elements (EREs). While EREs have been identified in several gene promoters and regulatory regions, it has been reported than more than one third of human genes regulated by estrogen receptors do not contain ERE sequence elements (O\'Lone, Frith, Karlsson, & Hansen, 2004). On the other hand, non-genomic effects involve indirect regulation of gene expression through a variety of intracellular signaling events. The known mechanisms for genomic and non-genomic control of gene expression by estrogens are described below.
Nuclear estrogen receptors: Direct genomic signaling Direct genomic signaling is known as the classical mechanism of estrogen signaling. In this process, the nuclear estrogen receptors ERα and ERβ act as ligand-activated transcription factors (Marino, Galluzzo, & Ascenzi, 2006; O\'Malley, 2005). Upon binding of estradiol to ERα or ERβ in the cytoplasm, a conformational change occurs inducing receptor dimerization (Le Dily & Beato, 2018(Fig. 7). This complex is then translocated to the nucleus, where it binds to the chromatin at ERE sequences, enhancer regions within or close to promoters, and/or 3′-untranlated regions of target genes (Klinge, 2001). Recent advances in computational biology have facilitated the identification of EREs in many gene promoters, and allowed prediction of genes regulated by estrogen and other hormones in the genomes of many species (Bajic et al., 2003; Bourdeau et al., 2004). A recent genome-wide screening study identified over 70,000 EREs in the human and mouse genomes (Bourdeau et al., 2004). Interestingly, 17,000 of these EREs were located near mRNA transcriptional start sites, and only 660 were conserved sites. The efficacy of this computational approach was further supported by functional validation of estrogen receptor interaction sites (Carroll & Brown, 2006). While these elements share a high degree of sequence similarity, it is important to recognize that the intrinsic sequence composition of the EREs can alter the affinity of the receptor to bind DNA. For example, ERα has a high binding affinity for the canonical ERE sequence located within the vitellogenin A2 gene, but with less affinity for the EREs located in the oxytocin gene (Sausville, Carney, & Battey, 1985). This moderately explains why differences in ERE sequences, such as those resulting from inter-individual gene variability or mutations, can affect the activation of gene expression (Loven, Wood, & Nardulli, 2001; Yi et al., 2002). In addition, specific ERE sequences can cause allosteric changes in the receptor\'s structure, and thus alter the ability of the complex to recruit coactivators and transcription factors that may contribute to ER biological activity (Hall, McDonnell, & Korach, 2002; Yaşar, Ayaz, User, Güpür, & Muyan, 2017).