Plasma Membrane Estrogen Receptors Exist and Functions as Dimers

Razandi, Mahnaz; Pedram, Ali; Merchenthaler, Istvån; Greene, Geoffrey L.; Levin, Ellis R.

doi:10.1210/me.2004-0115

Cited by 301 publications

(219 citation statements)

References 41 publications

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“…Razandi et al (1999) showed that identical membrane and nuclear ERa and ERb receptors of 67 and 54 kDa, respectively, could arise from a single ERa or ERb transcript expressed in CHO cells. Endothelial cells (EC) from an ERa/b double-KO lack membrane or nuclear ERa or ERb (Razandi et al, 2004). In contrast, a novel membrane-associated 63 kDa membrane ER-X, which cross reacts with anti-ERa antibodies, including MC20, has also been reported in an ERa-KO mouse (Toran-Allerand et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

The localization and non‐genomic function of the membrane‐associated estrogen receptor in oligodendrocytes

Hirahara

Matsuda

Gao

et al. 2008

Glia

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There is general acceptance that the estrogen receptor can act as a transcription factor. However, estrogens can also bind to receptors that are located at the plasma membrane and stimulate rapid intracellular signaling processes. We recently showed that a membrane-associated estrogen receptor (mER) is present within myelin and at the oligodendrocyte (OL) plasma membrane. To understand the physiological function of mER in OLs, we investigated its cellular localization and involvement in rapid signaling in CG4 cells and OL primary cultures. An ERa was expressed along the lacy network of veins in the membrane sheets and in the perikaryon and nucleus in OLs. ERb was located in the nucleus, and to a lesser extent along the veins. The expression of ERa and ERb in OL membranes was confirmed by Western analysis of isolated membranes. OL membranes mainly had truncated forms of ERa, 53 and 50 kDa, in addition to some 65 kDa form, whereas ERb was a 54 kDa form. CG4 cells and OLs were pulsed with 17a-and 17b-estradiol for various times and the total lysates were analyzed for phosphorylated kinases. Both 17a-and 17b-estradiol elicited rapid phosphorylation of p42/44MAPK, Akt, and GSK-3b within 8 min. This rapid signaling is consistent with estradiol ligation of a membrane form of ER. Since 17a-estradiol is produced at higher concentrations than 17b-estradiol in the brain of both sexes, signaling via 17a-estradiol-liganded mER may have an important function in OLs. V V C

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Section: Discussionmentioning

confidence: 99%

The localization and non‐genomic function of the membrane‐associated estrogen receptor in oligodendrocytes

Hirahara

Matsuda

Gao

et al. 2008

Glia

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“…In these studies, the nature of the membrane-bound estrogen receptor has been proposed to resemble ERa (Razandi et al 2004;Acconcia et al 2005), and the identity of the ERb localized to membranes remains controversial (Yang et al 2004(Yang et al , 2006. However, it also appears that there may be other novel estrogen receptors (e.g.…”

Section: Discussionmentioning

confidence: 99%

17‐β‐Estradiol‐mediated activation of extracellular‐signal regulated kinase, phosphatidylinositol 3‐kinase/protein kinase B‐Akt and N‐methyl‐d‐aspartate receptor phosphorylation in cortical synaptoneurosomes

Dominguez

Liu

Baudry

2007

Journal of Neurochemistry

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In addition to its well-known activational mechanism, the steroid hormone 17-b-estradiol (E2) has been shown to rapidly activate various signal transduction pathways that could participate in estrogen-mediated regulation of synaptic plasticity. Although the mechanisms underlying these effects are not clearly understood, it has been repeatedly suggested that they involve a plasma membrane receptor which has direct links to several intracellular signaling cascades. To further address the question of whether E2 acts directly at the synapse and through membrane-bound receptors, we studied the effects of E2 and of ligands of estrogen receptors on various signaling pathways in cortical synaptoneurosomes. Our results demonstrate that E2 elicits N-methyl-D-aspartate receptor phosphorylation and activates the extracellular signal-regulated kinase and the phosphatidylinositol 3-kinase/Akt signal transduction pathways in this cortical membrane preparation. Furthermore, we provide evidence for the presence of a membrane-bound estrogen receptor responsible for these effects in cortical synaptoneurosomes. Our study demonstrates that E2 directly acts at cortical synapses, and that synaptoneurosomes provide a useful system to investigate the mechanisms by which E2 regulates synaptic transmission and plasticity.

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“…These E2-activated responses are thought to be mediated through a membrane-associated population of classical ERs. ERα and ERβ are detectable in membrane fractions of breast cancer cells [46] and by immunohistochemistry (IHC) in breast tumor samples within and outside the nucleus [47]. In ER+ MCF7 cells, E2 increases ERα association with c-Src, Shc, and the IGF-1 receptor, ERα-dependent PI3 kinase activation, and proliferation [48][49][50].…”

Section: Crosstalk With Growth Factors and "Nongenomic" E2 Responsesmentioning

confidence: 99%

ERβ in breast cancer—Onlooker, passive player, or active protector?

2008

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The role of estrogen exposure in breast cancer risk is well-documented, and both estrogen synthesis and actions through the estrogen receptor (ER) have been targeted by therapies to control hormonedependent breast cancer. The discovery of a second ER form and its therapeutic implications sparked great interest. Both the original ERα and the more recently identified ERβ subtypes bind and respond similarly to many physiological and pharmacological ligands. However, differences in phytoestrogen binding have been noted, and subtype-specific ligands have been developed. Cell-based assays show that ERβ and its variants are generally less active on gene transcription than ERα, and may influence ERα activity; however, both gene-and cell-specific responses occur, and nongenomic activities are less well explored. Specific ligands, and methods to disrupt or eliminate receptor subtype expression in animal and cell models, demonstrate that the ERs have both overlapping and distinct biological functions. Overall, in cell-based studies, ERα appears to play a predominant role in cell proliferation, and ERβ is suggested to be antiproliferative.The potential for distinct populations of breast tumors to be identified based on ER subtype expression, and to exhibit distinct clinical behaviors, is of greatest interest. Several studies suggest that the majority of ER-positive tumors contain both subtypes, but that some tumors contain only ERβ and may have distinct clinical behaviors and responses. Expression of ERβ together with ERα favors positive responses to endocrine therapy in most studies, and additional studies to determine if the addition of ERβ to ERα as a tumor marker is of clinical benefit are warranted. In contrast, the positive association between ERβ and HER2 expression in high-grade ERα-negative breast cancer does not favor positive responses to endocrine therapy. Expression of ERβ in specific clinical subpopulations, and the potential for therapies targeting ERβ specifically, is discussed.

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Plasma Membrane Estrogen Receptors Exist and Functions as Dimers

Cited by 301 publications

References 41 publications

The localization and non‐genomic function of the membrane‐associated estrogen receptor in oligodendrocytes

The localization and non‐genomic function of the membrane‐associated estrogen receptor in oligodendrocytes

17‐β‐Estradiol‐mediated activation of extracellular‐signal regulated kinase, phosphatidylinositol 3‐kinase/protein kinase B‐Akt and N‐methyl‐d‐aspartate receptor phosphorylation in cortical synaptoneurosomes

ERβ in breast cancer—Onlooker, passive player, or active protector?

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