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The Estrogen Trinity: Membrane, Cytosolic, and Nuclear Effects

Angel Nadal¹, Mario Díaz² and Miguel A. Valverde³

¹ Institut de Bioenginyeria, Universitat Miguel Hernández, Campus de Sant Joan, 03550 Alacant;
² Laboratorio de Fisiologia Animal, Departamento de Biologia Animal, Universidad de La Laguna, 38206 Tenerife; and
³ Unitat de Senyalització Cellular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, C/Dr. Aiguader 80, 08003 Barcelona, Spain

	Abstract

 
Estrogens have a wide array of biological effects, targeting both genomic and nongenomic mechanisms. Classically, the estrogen receptors activating the transcription machinery in the nucleus were thought to be distinct from the extranuclear estrogen receptors. Recently, this conceptual wall has started to be dismantled as the result of the identification of novel routes of estrogen action.

	Introduction

Top Introduction Nuclear effects Membrane effects Direct binding to... Actions through a membrane... Actions through nonclassic ERs Cytoplasmic interactions Summary References

 
During the past two decades, we have witnessed a scientific revolution that has led to the identification of novel mechanisms of action for estrogens, typically termed "nongenomic estrogenic effects," a nomenclature that we consider inappropriate. Therefore, before continuing with the description of the different mechanisms of action, we would like to clarify a few concepts. We will refer to "nuclear effect" or "classic pathway" when the action of estrogen occurs at the nucleus, involving the direct participation of the estrogen receptors (ER) as transcription factors without other previous signaling steps required for estrogen action. All other mechanisms of action of estrogens will be named "alternative pathways." These alternative pathways might be initiated at either membrane or cytosolic locations and result in either direct local effects (e.g., modulation of ion channel activity and cell excitability) or effects such as the regulation of gene transcription secondary to the activation of signaling cascades [e.g., cAMP or mitogen-activated protein kinase (MAPK) cascades].

The first indication of the existence of alternative steroid actions was obtained by Hans Seyle in 1942, who reported the rapid anesthetic effects of progesterone, an effect now identified as the result of progesterone interaction with -aminobutyric acid (GABA) and/or glutamate ionotropic receptors. To date, the study of alternative actions of estrogens has been extended to a wide range of different tissues, helping us to understand the key roles of estrogens in the modulation of cell growth, proliferation, and differentiation as well as the regulation of the activity of organs as diverse as the uterus, ovary, testes, breast, bone, blood vessels, and brain. From these studies it is possible to identify typical characteristics of alternative mechanisms of action of estrogens: 1) the rapid time course (from seconds to minutes) of the primary effect is too fast to be compatible with either RNA synthesis or protein translation; 2) they might be dependent on the presence of classic ERs, a mechanism typically identified by the inhibition of the effect by specific ER antagonists such as ICI-182780, or might be ER independent, i.e., insensitive to ICI-182780; and 3) the extracellular membrane-delimited primary effect might be achieved by estrogen conjugated to membrane-impermeant molecules (usually large molecules like albumin or peroxidase), although this assumption must be cautiously approached because it is now recognized that these membrane-impermeant estrogen conjugates may have free estrogen associated with them.

The huge number of reports referring to nongenomic effects of estrogens has prompted the scientific community to find a way to classify such novel mechanisms of action. A first attempt at such a classification was launched at the First International Symposium on Rapid Responses of Steroid Hormones (3). The present article will discuss the estrogen effects depending on the cellular location of the primary estrogen action: membrane, cytosol, and nuclear effects. This review will also focus on the main mechanisms of action of estrogens at the three locations rather than an exhaustive listing of different effects of estrogens. For a comprehensive account of estrogen's effects, we refer the readers to two excellent reviews (1, 3).

	Nuclear effects

Top Introduction Nuclear effects Membrane effects Direct binding to... Actions through a membrane... Actions through nonclassic ERs Cytoplasmic interactions Summary References

 
Many of the members of the steroid/thyroid receptor family shuttle between the cytoplasm and the nucleus in the absence of ligands. On binding to the agonist, they translocate to the nucleus where, acting as a transcription factor, they initiate transcription (1). The binding of estrogen to the ER occurs with high affinity and promotes conformational changes in the receptor-protein complex and dimerization, leading to its activation. This process enables the complex to bind to selective sites on the DNA known as estrogen-responsive elements (ERE) within the promoter region of target genes. Through its binding to ERE, the activated estrogen-receptor complex triggers the synthesis of specific mRNAs and the production of a number of proteins that are responsible for the effects of the hormone in the different cell types (Fig. 1). There are two receptors identified so far: ER and ERß (8). The ERs are multidomain proteins with A-B domains containing a ligand-independent transcription activation function 1 (AF-1). The C region contains a highly conserved DNA binding domain with two zinc fingers that are essential for DNA binding. Domain D is the hinge region of the receptors, and domain E is responsible for specific ligand recognition and binding. The E domain also contains a ligand-dependent AF-2, and along with domain C it contains a 90-kDa heat shock protein binding function. ERß, of which different isoforms have been identified, shares high homology with ER in certain domains, such as the DNA binding domain, but differs in the ligand-binding domain and the NH₂ terminal A-B domains. These differences generated considerable interest because of the underlying assumption that ER and ERß would regulate different target genes. It was soon observed that they can give rise to opposing regulatory signals in response to 17ß-estradiol. There are also differences in the binding affinities for estrogenic substances. ERß receptors have a lower affinity for 17ß-estradiol than ER (8). ERs can form homo- or heterodimers, raising the possibility that ER and ERß act synergistically or as antagonists via homo- or heterodimerization on the activation step of a common responsive element.

View larger version (120K): [in this window] [in a new window]   FIGURE 1. Scheme of the different mechanisms of action of estrogens. Estrogen targets appear at 3 different cellular levels. First, there are membrane targets, including estrogen and receptor(s) related to the classic nuclear estrogen receptors (ER), nonclassic ERs, and ligand- and voltage-activated ion channels. The activation of some of these receptors triggers signaling events (e.g., intracellular messengers), resulting in the activation of different kinases. Second, there are cytosolic targets, mainly represented by the classic ER and ERß, which activate different signaling pathways. Activation of both membrane and cytosolic targets might ultimately determine a change in gene expression. Finally, there are nuclear targets, defined as the direct modulation of gene expression by the interaction of the ER-estrogen complex with the estrogen response element on the DNA. CREB, cAMP response element binding protein.

	Membrane effects

Top Introduction Nuclear effects Membrane effects Direct binding to... Actions through a membrane... Actions through nonclassic ERs Cytoplasmic interactions Summary References

 
In the past two decades, evidence has accumulated in favor of membrane effects of estrogens after interaction with the cellular surface (3). These membrane actions could conceivably be due to either a change in some membrane properties or to specific binding to membrane targets. Nonspecific effects are most commonly associated with a change in membrane fluidity. Nonetheless, concentrations at which nonspecific effects are manifested are, in general, supramicromolar and therefore will not be achieved in a physiological situation.

Specific effects after binding to membrane proteins have been studied in practically all physiological systems, including the endocrine, vascular, and nervous systems. Membrane proteins involved in rapid estrogen actions include specific ERs, ion channels, membrane enzymes, and other ligand receptors.

	Direct binding to neurotransmitter receptors and ion channels

Top Introduction Nuclear effects Membrane effects Direct binding to... Actions through a membrane... Actions through nonclassic ERs Cytoplasmic interactions Summary References

 
Steroids have been shown to act as allosteric coagonists or antagonists of neurotransmitter receptors. The best-known example is the allosteric modulation of the GABA_A receptor-chloride channel by neurosteroids, which mimics the effect of barbiturates. Allosteric modulation of neurotransmitter receptors by 17ß-estradiol has also been studied, and its relevance for the nervous system is highlighted by the modulation of synaptic activity by estradiol. Here, 17ß-estradiol behaves as an allosteric antagonist of N-methyl-D-aspartate receptors and 5-hydroxytryptamine receptors (3). Recently, the existence of an estrogen binding site within a voltage-gated ion channel has been demonstrated (15). Binding of 17ß-estradiol to an extracellular site of the ß-subunit of the large-conductance calcium-dependent potassium channel increases its activity, an effect that might explain, at least in part, the estrogen-induced acute vasodilation (14).

	Actions through a membrane receptor related to classic ER

Top Introduction Nuclear effects Membrane effects Direct binding to... Actions through a membrane... Actions through nonclassic ERs Cytoplasmic interactions Summary References

 
Following the Mannheim classification of nongenomic (alternative) steroid actions (3), two kinds of specific membrane steroid receptors might exist: 1) a membrane receptor with a molecular structure related to the classic steroid nuclear receptor and 2) a nonclassic steroid membrane receptor.

The existence of proteins in the plasma membrane that cross-react with antibodies raised against classic estrogen receptor ER has been described (discussed in Ref. 12). The membrane receptor involved appears to be very similar in structure to ER, since it is recognized by nine different antibodies raised against different epitopes of the ER. Moreover, expression of ER and ERß in Chinese hamster ovary cells demonstrate that both ER and ERß located at the plasma membrane are able to stimulate signaling pathways after interacting with G proteins, leading to the activation of phospholipase C and adenylyl cyclase, which increase inositol-1,4,5-trisphosphate and cAMP levels, respectively (13). Therefore, some of the membrane actions triggered by estrogens are likely mediated by a membrane receptor, with a structure resembling that of the classic ER. In respect to the localization of ER to the plasma membranes of cells overexpressing ER, a cautionary note should be taken into consideration. In our experience, overexpression of various proteins result in their unusual location, e.g., the presence in the plasma membrane of proteins normally found in intracellular locations.

	Actions through nonclassic ERs

Top Introduction Nuclear effects Membrane effects Direct binding to... Actions through a membrane... Actions through nonclassic ERs Cytoplasmic interactions Summary References

 
Classic ERs are not the only membrane receptors involved in the generation of an estrogen response. Strong evidence for the existence of different types of estrogen binding sites exists. 17ß-estradiol affects neuronal excitability in ER knockout mice (4). The possibility that ERß is responsible for 17ß-estradiol actions is ruled out by the absence of effect of the specific antiestrogen ICI-182780. It is now apparent that many of the membrane-delimited estrogen responses are mediated by the activation of phospholipase C/adenylyl cyclase pathways via the modulation of G protein-coupled receptors (7). However, the characterization and location of the membrane receptor involved in these types of responses has not always been possible. An example of successful identification of the membrane estrogen binding site has recently been reported for pancreatic ß-cells (Fig. 2). In this particular type of cell, 17ß-estradiol modulation of insulin secretion (12) is mediated by a membrane receptor with a pharmacological profile of the so-called -adrenergic receptor but unrelated to the classic ER, as manifested by immunohistochemistry and binding experiments (11). The effect of estrogen in pancreatic ß-cells determines the closing of ATP-dependent potassium channels and the subsequent potentiation of calcium signals and insulin secretion via the activation of a cGMP signaling cascade (discussed in Ref. 11).

View larger version (89K): [in this window] [in a new window]   FIGURE 2. Modulation of insulin secretion by estrogen. A: calcium imaging of a pancreatic islet of Langerhans exposed to 8 mM glucose and 1 nM 17ß-estradiol. The color image of a fluo 3-loaded islet shows the fluorescence intensity (blue corresponds to low and red to high intensity) of the peripheral cells, with the boundaries of each cell clearly visible. B: record of relative fluorescence intensity vs. time obtained from a cell within the islet shown in A. Note the increase in the calcium spikes triggered by the addition of 1 nM 17ß-estradiol. C: estrogen signaling in pancreatic ß-cells. Binding of 17ß-estradiol to the membrane -adrenergic receptor () activates a guanylyl cyclase (GC) and subsequently the protein kinase G (PKG)-dependent phosphorylation of ATP-sensitive potassium channels. The channel phosphorylation results in its closing, leading to membrane depolarization and opening of voltage-gated calcium channels. Calcium entry ultimately triggers insulin secretion. The effect of 17ß-estradiol, which requires the presence of glucose, potentiates the insulin secretion triggered by the latter.

"Estrogens...can also interact with targets within the cytosol."

Other examples of estrogen modulation of membrane properties involve the modulation of intracellular calcium homeostasis. Depending on the cell type, estrogens can either increase (12) or decrease (14) intracellular calcium levels. The actual mechanisms of action associated with calcium modulation by estrogens are not fully understood, but both modulation of intracellular calcium stores and regulation of plasma membrane calcium channels have been proposed.

	Cytoplasmic interactions

Top Introduction Nuclear effects Membrane effects Direct binding to... Actions through a membrane... Actions through nonclassic ERs Cytoplasmic interactions Summary References

 
Estrogens, in addition to their actions at the membrane and nuclear locations, can also interact with targets within the cytosol. In this section, we will briefly discuss the nature of these cytosolic targets. One of the best-studied examples of cytosolic actions of estrogens is the activation of the Src/Ras/extracellular signal-regulated kinase (ERK; also known as MAPK) pathway (10), a mechanism of action that might be related to the proliferative effect of estrogens.

Under nonstimulatory conditions, the catalytic domains of the Src kinase are in an inactive state as a result of intramolecular interactions. Binding of estradiol to either cytosolic ER or ERß receptors determines the interaction of ER with Src, changing the conformation of the kinase to an active state and the activation of the Src/Ras/ERK signaling cascade. Similar results have also been reported for the androgen and progesterone receptors (10), although the latter requires the participation of the ER as well. These studies provide a good example of cross-talk between different steroid receptors as well as between different signaling pathways, i.e., estrogens activate the signaling pathways (Src/Ras/ERK) normally associated with growth factors (e.g., epidermal growth factor or insulin). Moreover, there is a real two-way cross-talk, because many growth factors (6) have been involved in ER activation in the absence of estradiol, normally via the phosphorylation of ER. However, the ability to induce ER-mediated transcription in response to growth factors depends on the cell context and on the target genes.

Another example of a cytosolic effect of estrogen is the modulation of nitric oxide (NO) bioavailability in vascular cells. Estrogen's effects on the vasculature are related to a reduced risk of coronary heart disease in women (discussed in Ref. 9). These vascular effects involve both the systemic modulation of lipid metabolism and local effects leading to vasodilation (9). The latter has been shown to include rapid increase in the production of the vasodilator NO (9) and/or the modulation of smooth muscle ion channels (14). It is known that estrogen activates endothelial NO synthase (eNOS, the enzyme responsible for NO production) without altering its expression in vascular endothelium, an effect that appears to require ER with an intact hormone-binding domain. This effect cannot be reproduced by binding of estrogen to ERß (5), although both forms (ER and ERß) are expressed in vascular cells (9). The activation of NOS by estrogen has been classically associated with the interaction of estrogen with a plasma membrane receptor, a hypothesis supported by the fact that nonpermeable estrogen conjugated to albumin also reproduces the effect. Recent reports (Ref. 5 and references therein) have demonstrated that the activation of NOS in endothelial cells by ER involves phosphatidylinositol 3-kinase (PI3K), and Chambliss and co-workers (2) have localized functional ER-eNOS signaling complex to endothelial caveolae. These structures form signal-transducing membrane microdomains that, in endothelial cells, in addition to ER and eNOS, also contain PI3K. This new, and very interesting, model for signal transduction moves the site of action of estrogen from the external to the internal side of the membrane. Binding of estrogen to the ER via a direct physical interaction with the regulatory p85 subunit of PI3K activates serine/threonine protein kinase B (also termed Akt), which in turn will phosphorylate and activate NOS (5). However, there are still observations that require further study to fully understand the role of ER in the activation of NOS. It seems that activation of NOS by estrogen, like the activation of the Src/Ras/ERK pathway described above, requires calcium (5). Typically, a calcium peak precedes the increase in NO production. How can we integrate these two observations? Does estrogen, alone or bound to ER, mobilize calcium before interacting with PI3K? These are questions that, undoubtedly, will be resolved in the near future.

	Summary

Top Introduction Nuclear effects Membrane effects Direct binding to... Actions through a membrane... Actions through nonclassic ERs Cytoplasmic interactions Summary References

 
The existence of one of the three mechanisms in a particular cell is not exclusive. In this way, estrogens can elicit diverse cellular effects that may depend on their concentration because most of the estrogen binding sites present different affinities. In general, binding to ion channels and allosteric effects through other ligand receptors are triggered at supraphysiological doses, which could be achieved locally or after accumulation in the lipid bilayer. Other properties of estrogens, e.g., antioxidant properties, also occur at supraphysiological concentrations. Actions via binding to putative membrane ER are produced at concentrations within the physiological range (10^–12–10^–9 M). Nonetheless, high estrogen concentrations might be reached locally in certain areas of the brain, and the lipophilicity of steroids would contribute to the enrichment of estrogens at the membrane-receptor interface.

In the future, binding sites are likely to be identified in different channels or membrane receptors, and the molecular mechanisms of estrogen action at the three cellular compartments will be unveiled. This knowledge will help us to understand the endocrine regulation of different body systems.

	Acknowledgments

 
We gratefully acknowledge the support of CICYT/FEDER (A. Nadal and M. Diaz), Fundación Navarro-Tripodi (A. Nadal), and the Human Frontiers Science Program, Spanish Ministry of Science and Technology and Distinció de la Generalitat de Catalunya per a la Promoció de la Recerca Universitaria to M. A. Valverde.

	References

Top Introduction Nuclear effects Membrane effects Direct binding to... Actions through a membrane... Actions through nonclassic ERs Cytoplasmic interactions Summary References

 

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