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Departments of Anatomy and Cell Biology, and Neurology, and Centers for Neurobiology and Behavior, and Reproductive Sciences, Columbia University College of Physicians and Surgeons, New York, New York 10032
Address all correspondence and requests for reprints to: C. Dominique Toran-Allerand, Department of Anatomy and Cell Biology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. E-mail: cdt2{at}columbia.edu.
Abstract
Until 1996, when estrogen receptor (ER)-ß was discovered, life seemed simple. The gonadal steroid hormone 17ß-estradiol had one receptor, the ER, a ligand-inducible nuclear transcription factor. ER variants, the result of base pair insertions, transitions, and deletions, as well as alternative splicing, were considered abnormal and a prominent feature of breast cancer. Since then, like many other scientific beliefs, this concept has increased dramatically in complexity, and we are now faced with an ever-increasing array of estrogen-binding proteins, putative ERs, in the brain as well as in the extraneural targets of estrogen. The end is unlikely to be in sight. Some of these putative receptors have been localized to plasma or nuclear membranes, and others to the cytoplasm and/or nucleus. The molecular characteristics of membrane ERs are still in question, and, in most instances, the proteins have not been sequenced or cloned. However, based on transfection and immunohistochemistry, the generally held view, if not dogma, maintains that both nuclear and plasma membrane-associated ERs probably originate from the same gene and transcript that produce the classical intranuclear receptors ER-
and ER-ß. However, the physiological relatedness of this observation remains open to question. This review addresses evidence that, in addition to ER- and ER-ß, there exist a variety of non-ER-/non-ER-ß nuclear, cytoplasmic, and plasma membrane ERs in the brain, including G protein-coupled receptors; a novel, developmentally regulated, membrane-associated ER, ER-X; a functional, truncated ER- variant, ER-46; and a putative ER that is immunochemically, structurally, and functionally completely distinct from ER- and ER-ß.
Discovery consists not in seeking new landscapes but in having new eyes. —Marcel Proust
BESIDES ITS WELL-ESTABLISHED organizational and activational actions on reproductive neuroendocrine function, estrogen also exerts a wide variety of actions on regions of the developing and adult brain that influence higher cognitive functions, pain mechanisms, fine motor skills, susceptibility to seizures, mood, temperature regulation, and sleep (1, 2). Despite the current journalistic hype surrounding the results of the Women’s Health Initiative studies, clinical and experimental studies have shown that estrogen also has neuroprotective effects with respect to damage from Alzheimer’s and Parkinson’s diseases, multiple sclerosis, major depression and bipolar disorder, schizophrenia, and ischemic stroke (3, 4, 5, 6). For at least three decades, this plethora of estrogenic actions in the brain was believed to be mediated by a single, ligand-activated transcription factor, the intranuclear estrogen receptor (ER) (7). The discovery in 1996 of a second form of the ER in rat prostate (8, 9), termed ER-ß (the original ER is now referred to as ER-), changed this view completely and opened a Pandora’s box from which has emanated an increasing number of estrogen-binding proteins, putative ERs, often classified as alternative splicing variants; but some may even be new genes. A third, more distantly related member of the ER family, ER-
, has also recently been cloned and is found only in teleosts (10).
The Classical Intranuclear ERs
Most of estrogen’s known transcriptional actions in mammals are mediated by the classical receptor ER- (7) and the more recently cloned ER-ß (8, 9) whose role remains largely uncharacterized but may be modulatory. ER- and ER-ß are members of the nuclear receptor superfamily of ligand-inducible transcription factors whose family members include the steroid, thyroid hormone, retinoic acid, vitamin D, and nuclear orphan receptors (11, 12, 13). Under steady-state conditions, these receptors are predominantly intranuclear. ER- and ER-ß appear to be complementary but not redundant and are genetically and functionally distinct. It has been suggested that an important physiological role of ER-ß is to modulate ER--mediated gene transcription by inhibiting ER--mediated gene transcription in the presence of ER-, and partially replacing ER- in its absence (14). Although ER- and ER-ß share DNA binding domains (97%), they differ somewhat with respect to their ligand-binding domains (LBDs) (60%) and bear virtually no homology within their N-terminal regions (9). ER- and ER-ß also differ to varying extents with respect to their binding affinities and ligand specificities and have distinct spatiotemporal patterns of expression (15). In the brain, for example, whereas neocortical ER-ß is present throughout life (16), neocortical ER- expression is developmentally regulated and normally expressed at very high levels only during the period of neocortical differentiation (17), suggesting a more restricted developmental role.
ERs are kept in the inactive state by forming a complex with heat shock protein 90 (hsp90) (for reviews, see Refs. 12 and 13). In the traditional view of estrogen action, exposure of a target cell to estrogen initiates activation of its receptor and triggers a cascade of intracellular events, which includes phosphorylation on serine and tyrosine residues, dissociation of the ER from hsp90 with which the unbound receptor is complexed, and receptor dimerization (18). These multiple steps result in the direct interaction of the hormone-activated receptor dimers with a specific cognate regulatory DNA sequence in the promoter region of target genes [the estrogen response element (ERE)] or with other transcriptional factors (18, 19, 20) to regulate a wide variety of transcription factors, genes, and gene networks by either enhancing or suppressing their function.
Membrane-Associated ERs
Some estrogenic effects, however, cannot be attributed to ER- or ER-ß, which suggests the existence of additional subtypes. The traditional view of estrogen action explains inadequately the complete and extensive range of estrogen’s actions in the brain, including the ability of estrogen to regulate many genes that do not exhibit an apparent ERE (21). In this regard, Kushner et al. (22) have shown that ERs not only bind to EREs in target genes to recruit a coactivator complex of cointegrator-associated protein-p160 that mediates stimulation of transcription but can also activate transcription at activator protein-1 sites that bind the Jun/Fos transcription factors via the activation protein-1 (AP-1) (23). Equally poorly explained are the mechanisms that underlie the very rapid effects of estrogen that occur within seconds to minutes (24, 25, 26, 27). Such a rapid time course appears inconsistent with direct transcriptional modulation via classical intranuclear receptors, a process whose latency, although quite variable and dependent upon the size of the transcript and gene, nonetheless tends to be significantly longer than the seconds to minutes seen for the rapid effects of estrogen. For example, following aldosterone exposure, early genes were expressed 1 h after its addition (28). On the other hand, such rapid effects of estrogen could be explained by the presence of plasma membrane-associated ERs that may be coupled to downstream signal transduction pathways typically associated with rapid activation by growth factors, and in this way lead indirectly to the regulation of genes and transcription factors.
The existence of membrane-associated ERs has been highly controversial since 1977, when Pietras and Szego (29) described specific binding sites for estrogen at the outer surfaces of isolated endometrial cells. Controversy has persisted because of failures to isolate and characterize such a membrane-associated receptor protein(s). Nonetheless, strong functional evidence now exists for the presence and importance of plasma membrane ERs in a wide variety of neural and extraneural target cells of estrogen. Although ER- and ER-ß are thought to be largely intranuclear, plasma membrane-associated ER- and ER-ß have also been described (30, 31, 32). The prevailing view, if not dogma, maintains that both nuclear and plasma membrane-associated ERs probably originate from the same gene and transcript that produce ER- and ER-ß (30, 33). However, because this view is based largely on transfections of ER- or ER-ß into cells [CHO-K1 (30) and Rat2 fibroblasts (31)] that do not normally express these receptors, the extent to which such findings represent the physiological condition in cells that normally do express ER- or ER-ß is unknown. All the more so because we have recently shown that transfection of ERs into CHO-K1, COS-7, and Rat2 fibroblast cell lines is not necessary for rapid estradiol activation of the MAPK cascade (34). Contrary to the generally held opinion, these cell lines are not unresponsive to estradiol in their native, nontransfected state. Moreover, their estrogen responsiveness is associated with high-affinity estrogen binding (Kd, 1.8 nM), and with a wide variety of variously sized, specific protein bands on Western blots, which are immunoreactive with antibodies to ER- and ER-ß. These bands range in molecular mass from 32–76 kDa (CHO) and 32–109 kDa (Rat2), but do not include bands of 66/67 kDa (ER-), or 55–60 and 64 kDa (ER-ß) (34). Although the nature of these ER--like immunoreactive bands is unknown, they appear to be specific, because they can fully blocked by preadsorbtion with the immunizing peptide. Their association with the plasma membrane suggests that that they may represent novel, membrane-associated, estrogen binding sites.
Caveolae and Caveolar-Like Microdomains (CLMs) of the Plasma Membrane
In neurons, plasma membrane receptors have been reported to localize mainly to discrete CLMs (35). CLMs are the neuron-specific homologs of caveolae (36, 37, 38), which are microdomains associated with the plasma-membrane of most cell types other than neurons. Unlike caveolae proper, CLMs express the integral membrane protein flotillin (39) abundantly rather than the caveolar protein caveolin, whose expression in the brain is restricted to astrocytes and microglia (40). CLMs, like caveolae, are highly enriched in cholesterol, glycosphingolipids, sphingomyelin, and lipid-anchored membrane proteins, and have been implicated in signal transduction and lipid/protein trafficking. Some of the proteins reportedly concentrated within these aptly named "crowded little caves" (36), for example, include, among many others: 1) the classical ERs ER- and ER-ß, and the ER- variant ER-46 (41, 42, 43), 2) receptor tyrosine kinases (e.g. the neurotrophin, insulin, epidermal growth factor and platelet-derived growth factor receptors), 3) the low-affinity neurotrophin receptor p75NTR, 4) hsp90, 5) the src family of tyrosine kinases, 6) the docking/adaptor proteins Shc and Grb2, 7) signal transduction molecules such as members of the MAPK cascade [Ras, B-Raf (Rap1), MAPK kinase, and ERK], adenyl cyclase, protein kinase A, and protein kinase C, 8) G proteins and G protein-coupled receptors, 9) lipid signaling molecules, 10) endothelial nitric oxide synthase, 11) the amyloid precursor protein (44), and 12) glycosylphosphatidylinositol-anchored proteins. This pattern suggests that CLMs and caveolae may serve as functional signaling modules to compartmentalize, modulate, and integrate signaling events at the cell surface (37, 38).
Novel Membrane ERs
Although there is some evidence that transfected ER- and ER-ß may also behave as plasma membrane receptors (30, 31, 45), other studies document the involvement of novel plasma membrane ERs that are 1) neither ER- nor ER-ß (46, 47, 48), 2) G protein-coupled receptors (49, 50, 51, 52), as well as 3) even an entirely different gene product with no relation to classical nuclear ERs that is structurally unique and exhibits intrinsic, ligand-stimulated, tyrosine kinase activity, as do growth factor receptors (53).
Reports of novel ERs are not new, although their identity has been based primarily on functional responses to estradiol, such as modulation of Ca2+ flux and K+ channel activation (27) and activation of a variety of signal transduction pathways. Das et al. (47) showed that the effect of the catecholestrogen 4-hydroxyestradiol on uterine lactoferrin expression was not only mediated by a potentially novel ER but that ICI 182,780 inhibited this effect in wild-type, but not in ER- gene-disrupted [ER knockout (ERKO)] tissue. Insensitivity to ICI 182,780 as well as to inhibitors of transcription and translation appears to be a feature of many rapid effects of estradiol on membrane receptors of both neural and extraneural targets that are not related to classical ER- and ER-ß (46, 47, 48). Other studies also support the existence of novel, ICI-insensitive ERs in the rapid and so-called nongenomic actions of estradiol in the brain (46, 47, 54). For example, 17ß-estradiol-induced potentiation of kainate-induced currents was not blocked by ICI 182,780 in isolated hippocampal CA1 neurons of both wild-type and ERKO mice (46, 54). Similarly, high-affinity estrogen binding sites in pancreatic ß-cells (48) and 17- and 17ß-estradiol activation of the MAPK family members ERK1 and ERK2 in neocortical explants were not blocked by the ICI compound (55). Although one may question whether the inability to block with the ICI compound is more likely the result of a nonspecific membrane effect than a characteristic of certain novel plasma membrane receptors, it should be pointed out that the ICI-insensitive receptors described above appear to be novel, high-affinity estrogen binding sites. Moreover, blocking by ICI 182,780 may not even be a universal response of the classical ERs. Thus, whereas ICI 182,780 decreased the expression of ER- in rat testis and its efferent ductules, it was without effect on testicular ER-ß (56). There is even a report of regional variations in antagonism by ICI 182,780 (57).
On the other hand, it has been reported that estrogen activation of cAMP response element-binding protein (58) and estrogen-mediated neuroprotection against ß-amyloid toxicity (59) were completely blocked by ICI 182,780. Although this may well suggest an ER-- or ER-ß-dependent mechanism, it should be pointed out that, in both studies, the cell lines used were stably transfected with ER- or ER-ß, which, not surprisingly, would be blocked specifically by the ICI compound.
ER-X
To add to this increasing ER complexity, we have recently identified a novel and unique, plasma-membrane-associated putative ER that is neither ER- nor ER-ß. I have designated this ER, ER-X (60). ER-X is developmentally regulated and highly enriched in purified CLMs of postnatal d-7, but not adult, neocortical plasma membranes not only of wild-type, but also of ERKO (56) and, most importantly, of ER--null (61) mice (Nethrapalli, I., and D. Toran-Allerand, unpublished observations).
We have also recently identified ER-X in the neocortex, hypothalamus, cerebellum, and lung of the term fetal baboon (Nethrapalli, I., and D. Toran-Allerand, unpublished observations). The apparent molecular mass of ER-X (
62–63 kDa) in the rat, mouse, and baboon differs from that of ER- (67 kDa) and ER-ß (54–60 and 64 kDa). In developing neocortex, ER-X sometimes appears as a 62- to 64-kDa doublet. The 62-kDa portion is developmentally regulated, whereas the 64-kDa band may be found in the adult (Nethrapalli, I., and D. Toran-Allerand, unpublished observations). Mass spectroscopy, which is currently in progress, will definitively establish the molecular mass of ER-X.
ER-X binds [3H]estradiol with high affinity but with binding properties and ligand specificities quite distinct from ER-: its Kd of 1.6 nM is approximately one order of magnitude less than that of ER- and ER-ß. Although 17-estradiol and 17ß-estradiol compete equally well for binding; progesterone competes (50%) for membrane estradiol binding. This differs completely from the inability of progesterone to displace estradiol from ER-.
Notwithstanding its immunoreactivity with antibodies to the C-terminal region of ER- or the fact that an oligonucleotide probe to that same portion of the C-terminal region of ER- hybridizes to ERKO neocortical neurons, ER-X is clearly not ER- (60). ER-X exhibits some but not complete homology with the ER- LBD, but has no homology with the N-terminal region. Thus, although the ER- and ER-X proteins can be identified with the same antibodies to the ER- LBD (MC20 antibody; Santa Cruz Biotechnology, Santa Cruz, CA), the immunoreactive ER- band on a Western blot, for example, can be blocked completely by a 200- to 500-fold excess of the blocking MC20 peptide, whereas the immunoreactive MC20 ER-X band requires a 2000-fold excess (10 times more) of the peptide to be blocked fully.
ER-X is the receptor that mediates 17-estradiol and 17ß-estradiol activation of MAPK/ERK in developing neocortical explants, whereas ER-- and ER-ß-selective ligands do not elicit activation of MAPK/ERK and are either inhibitory (ER-) or without effect (ER-ß) (60). Although both 17-estradiol and 17ß-estradiol bind ER-X, 17-estradiol appears to be the endogenous ligand of ER-X and activates MAPK/ERK at 1 pM. Significantly higher levels of 17ß-estradiol are required for ERK activation in wild-type neocortex, perhaps reflecting the need to overcome, in addition, the inhibitory effect of ER-, which, unlike 17-estradiol, 17ß-estradiol activates as well (60). As found with other constitutive membrane ERs, rapid activation of MAPK/ERK is not blocked by inhibitors of transcription or translation or the selective ER-/ER-ß antagonist ICI 182,780. Moreover, many characteristics of ER-X are the complete opposite of those attributed to ER- and ER-ß. For example, association of ER-X with hsp90 is an absolute requirement for estradiol activation of MAPK/ERK (62), whereas, in contrast, association with hsp90 is required to keep ER- in the inactive state (12, 13, 63).
Preliminary studies (Sétáló, Jr., G., and D. Toran-Allerand, unpublished observations) suggest that ER-X has features of a G protein-coupled receptor. Pretreatment of neocortical explants with low doses of pertussis toxin (1 ng/ml, for 60 min), but not cholera toxin (1 µg/ml, for 60 min), completely abrogated the ability of 17- and 17ß-estradiol to elicit ERK1/2 phosphorylation. This pattern is consistent with possible involvement of Gß subunits of the Gi/o family and is also supported by preliminary results that suggest that 17-estradiol and 17ß-estradiol increase guanosine 5'-O-3-thio-triphosphate membrane binding, a prominent feature of G protein-coupled receptor activation by agonists. ER-X is up-regulated in adult mouse models of Alzheimer’s disease and Down’s syndrome (our unpublished observations), in adult ischemic brain injury (60) and in the pregnant uterus, from which it disappears shortly after parturition (Nethrapalli, I., and D. Toran-Allerand, unpublished observations). Based on analyses using 5' rapid amplification of cDNA ends and RT-PCR (Tinnikov, A., and D. Toran-Allerand, unpublished observations), the evidence thus far suggests that ER-X is not an alternative splicing variant of ER- or ER-ß and may be a new gene. However, definitive proof awaits cloning the gene and sequencing the protein, which are both currently in progress.
Still More ERs
Other putative estrogen-binding proteins have also been identified in the brain. These include the identification of 112- and 116-kDa ERs in the adult rat cerebral cortex whose levels change with age and hormonal treatment but whose function is unknown (64). Ramirez and colleagues (65, 66, 67) have identified three membrane estrogen-binding proteins: 1) a 37-kDa protein with 100% homology with glyceraldehyde-3-phosphate dehydrogenase (65, 66), 2) a 55-kDa protein identified as ß-tubulin whose binding was completely displaced by 17ß-estradiol at 10-7 M (65), and 3) a 23-kDa protein identified as the oligomycin-sensitivity conferring protein (67). Their roles in estrogen-mediated actions are similarly unknown.
In addition, a 46-kDa amino-terminal truncated product of full-length ER-, ER46, has been identified in the plasma membrane, cytosol, and nucleus of resting, estrogen-deprived, nonneural cells (43), but does not seem to have been sought for in the brain. ER46 modulates membrane-initiated estrogen actions, including endothelial nitric oxide synthase activation in endothelial cells, which it reportedly does more efficiently than full-length ER- (43).
Complicating matters is the recent identification in the brain and other tissues of a heterodimeric estrogen-binding protein, termed the putative ER (pER) (81–84 kDa) (68). pER consists of two covalently bound subunits (61–67 and 17–27 kDa) and has been localized on the plasma or nuclear membrane of some cells, and in the cytoplasm and/or nucleus of others. pER has a high affinity for 17ß-estradiol (Kd, 0.7 nmol) but does not bind other natural steroids, synthetic estrogens, or antiestrogens. A serine phosphatase, this receptor is immunochemically, structurally, and functionally completely distinct from ER-, ER-ß, or ER-. Immunoreactive pER is undetectable in reproductive organs (except the ovary), but has been localized in brain, muscle, blood vessels, and retina, as well as in mammary, endometrial, and prostate tumors. Anti-pER antibodies do not recognize ER- or ER-ß, whereas antibodies to ER- or ER-ß do not react with pER. Immunosuppressants, neuroleptics, and carcinogens influence [3H]estradiol binding to pER. The anti-pER antibody reacts with calcineurin, a brain phosphatase, and anticalcineurin antibodies react with pER. It has been suggested that pER may mediate estrogenic actions in nonreproductive organs.
Light-Microscopic and Ultrastructural Localization of ERs
Specific binding of estrogen to the plasma membrane in brain was first shown in the 1980s by [3H]estradiol binding to synaptic membranes (69). Since then, numerous studies, particularly in the hippocampus and hypothalamus, have documented plasma membrane and cytoplasmic localization of ER- immunoreactivity at both light-microscopic (70, 71, 72) and electron-microscopic levels (73, 74, 75). ER--labeled profiles have been described as unmyelinated axons, axon terminals containing numerous small, synaptic vesicles, dendritic spines, and astroglial processes. Within dendritic spines, most ER- immunoreactivity has been seen in plasmalemmal and cytoplasmic regions of the spine heads and interpreted as plasma membrane ER- (73, 74, 75). However, the discovery of ER-X, which, like ER-, has also been localized to the plasma membrane of dendritic spines with many of the same antibodies (Fig. 1
; Ref. 60), makes this interpretation open to question, particularly in the developing brain. The unfortunate but inevitable reliance on immunoreactivity to identify ER phenotypes has increased this confusion, because the antibodies to ER- most frequently used are directed against the LBD of ER- and recognize not only ER- but ER-X as well as the ER--like immunoreactive bands in CHO, COS, and Rat2 fibroblasts.
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The nature of the receptor(s) involved in rapid estrogen actions remains elusive, and trying to unravel the receptors mediating these responses in the brain has proved daunting. This problem is compounded by the possibility that there may be a variety of additional membrane estrogen binding sites in the brain unrelated to ER- and ER-ß or to those described above, similar to the catecholaminergic receptor of pancreatic ß-cells (48) and the 29-kDa membrane ER of sperm (76). If the membrane ERs of these extraneural estrogen targets are any indication, there may well be additional membrane ERs in the brain whose identity may vary with brain region, cellular phenotype, and developmental stage. The identification of a plethora of putative ERs in the brain suggests that one should keep a very open mind and radically revise the current view of estrogen actions in developing and adult estrogen target tissues, both with respect to the estrogens that elicit them and the receptors, other than ER-- and ER-ß, that may mediate them.
Footnotes
This work was supported in part by grants from National Institutes of Health (National Institute on Aging), National Institute of Mental Health, and National Science Foundation; an Alzheimer’s Association/TLL Temple Foundation Discovery Award; and an Alcohol, Drug Abuse, and Mental Health Administration Research Scientist Award.
Abbreviations: AP-1, Activation protein-1; CLM, caveolar-like microdomain; ER, estrogen receptor; ERE, estrogen response element; ERKO, ER knockout; hsp90, heat shock protein 90; LBD, ligand-binding domain; pER, putative ER.
Received October 29, 2003.
Accepted for publication November 25, 2003.
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