Additionally although the membrane localized ER signaling

Additionally, although the membrane-localized ER signaling described in this review has generally been studied in isolation from nuclear signaling, it is becoming clearer and clearer that integration of these mechanisms must be considered (Frick, 2015). Perhaps the distinct estradiol signaling mechanisms serve as a sort of coincidence detector in various systems, whereby the convergence of rapid and slow effects promotes a certain outcome. This can be seen in the case of sexual receptivity, as both the slower and more rapid effects of estradiol are required in the hypothalamus for the normal expression of sexual receptivity in females (Kow and Pfaff, 2004). Specifically, ERα/mGluR1a signaling leads to rapid internalization of μ-opioid receptors in the medial preoptic area (Dewing et al., 2007), followed by a slower, enduring increase in dendritic spine density in the arcuate nucleus (Christensen et al., 2011). Similarly, estradiol signaling through ERα/mGluR5 affects neuronal excitability in striatal cells on the order of seconds or minutes (Grove-Strawser et al., 2010), followed by slower effects on dendritic spine plasticity (Peterson et al., 2014). These differing time courses converge to enhance motivated behaviors in females, as seen in the findings from our lab and others on estradiol facilitation of cocaine-induced plasticity. Although nuclear estrogen receptors are not found in abundance in the NAc, nuclear ERs in other reward circuitry neuronal metabolism regions could contribute to the effects of estrogens on the development and maintenance of addiction. Thus, it stands to reason that nuclear estradiol signaling adds another layer to the processes discussed in this review, and careful work must be undertaken to dissect these signaling mechanisms. Doing so will help explain the special nature of the ER/mGluR relationship that allows estradiol to powerfully influence neuronal physiology, structure, and, ultimately, behavior.
Introduction A better understanding of the molecular mechanisms underlying food functionality is crucial to our knowledge of potential health risks and benefits. However, such studies are often time consuming and expensive. Therefore, the application of in silico modelling studies to investigate receptor-mediated mechanisms might be useful in exploring food component functionality. In this paper, we will focus on estrogen receptor (ER)-mediated mechanisms of food functionality and the use of in silico molecular modelling (Schrödinger platform) to give insights into the potential benefits and risks of estrogen-mimicking (xenoestrogen) food components. ERs occur as two isoforms (ERα and ERβ) and are present in many cell types (Heldring et al., 2007); e.g. ERα predominates in mammary cells and ERβ in colon cells (Kuiper et al., 1997). ERs are important in growth and development (Mosselman et al., 1996) with functions far exceeding the conventional concepts of sex hormone receptors (Ye et al., 2018). The most potent natural ligand of ERs is 17β-estradiol (E2, Fig. 1) and when bound to the receptor it initiates a sequence of events that leads to regulation of genes involved in growth and development and expression of sexual characteristics (Reid et al., 2002). In order to activate ERs the ligand ideally has two hydroxyl groups, which hydrogen bond to amino acid residues in the ligand binding cleft (LBC), separated by 9.6 Å of hydrophobicity (Brzozowski et al., 1997). Molecules with similar molecular attributes (i.e. estrogen mimics) activate ERs, but to a lesser extent than E2. For example, the estrogen mimic genistein (a phytoestrogen; Fig. 1) from soy has a hydroxyl separation of 11.6 Å: genistein has a relative estrogenicity of 3.9 × 10−5 (where E2 = 1) (Berckmans et al., 2007) because its ER binding characteristics are not ideal. Flavonoids are important food components; they include subclasses based on their chemical structures; for example, flavone, flavonol, and isoflavone (Table 1). Flavonoids are present in many commonly consumed fruits, vegetables and herbs (e.g., apigenin in parsley, quercetin in red onion, genistein in soy, bergamottin in grapefruit) (Bailey et al., 2003), and can mimic E2 (Fig. 1) and thus activate ERs (Harris et al., 2005). The binding affinities of both E2 and estrogen mimics to ER isoforms are different this means that they will have differential tissue-based biological activity which is dependent on the distribution of ER isoforms in the tissue (Kuiper et al., 1997). Interestingly, ERβ (predominates in colon cells) (Kuiper et al., 1997) provides a more suitable binding environment for flavonoids and so might play an important role in flavonoid-containing colon-mediated food functionality.