Differential expression of estrogen receptor beta splice variants in rat brain: identification and characterization of a novel variant missing exon 4

Price, Richard H.; Lorenzon, Nancy M.; Handa, Robert J.

doi:10.1016/s0169-328x(00)00135-2

Cited by 83 publications

(71 citation statements)

References 34 publications

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“…In the plasma membrane of a human EC line, a truncated 46 kDa receptor was the predominant ERa isoform; palmitoylation induced its translocation to the plasma membrane (Li et al, 2003). At least five splice variant isoforms of the rat ERb gene product also have been reported (Al-Bader, 2006;Petersen et al, 1998;Price et al, 2000;Saji et al, 2001). Our data showed an 54 kDa band in membrane and cytosol fractions of OLs (Fig.…”

Section: Discussionsupporting

confidence: 60%

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: Discussionsupporting

confidence: 60%

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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“…ERbeta protein may be expressed as a number of different splice variants in brain tissues (Petersen et al 1998;Price et al, 2000), raising the distinct possibility that differential responses to estrogen may be mediated by differing splice variants of ERbeta (for review see Weiser et al, 2007). The originally described estrogen receptor beta is now more appropriately termed ERbeta1 and at least 5 different splice variants of ERbeta have been described.…”

Section: -β-Diol Regulation Of the Hpa Axismentioning

confidence: 99%

“…The originally described estrogen receptor beta is now more appropriately termed ERbeta1 and at least 5 different splice variants of ERbeta have been described. These include a beta2 variant which contains an 18 amino acid insert in the ligand binding domain, a delta3 variant where transcription of exon three is skipped resulting in a protein that does not bind DNA and a delta 4 variant where the fourth exon is skipped resulting in a protein that is largely cytoplasmic in localization (Petersen et al, 1998, Price et al, 2000. Different combinations of these splice variations can exist within a given receptor protein and differing combinations of receptor variants can exist within a cell thereby altering the way in which an estrogenic signal might be transduced (Weiser et al, 2007).…”

Section: -β-Diol Regulation Of the Hpa Axismentioning

confidence: 99%

An alternate pathway for androgen regulation of brain function: Activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5α-androstane-3β,17β-diol

Handa

Pak

Kudwa

et al. 2008

Hormones and Behavior

183

122

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The complexity of gonadal steroid hormone actions is reflected in their broad and diverse effects on a host of integrated systems including reproductive physiology, sexual behavior, stress responses, immune function, cognition, and neural protection. Understanding the specific contributions of androgens and estrogens in neurons that mediate these important biological processes is central to the study of neuroendocrinology. Of particular interest in recent years has been the biological role of androgen metabolites. The goal of this review is to highlight recent data delineating the specific brain targets for the dihydrotestosterone metabolite, 5α-androstane, 3β, 17β-diol (3β-Diol). Studies using both in vitro and in vivo approaches provide compelling evidence that 3β-Diol is an important modulator of the stress response mediated by the hypothalmo-pituitary-adrenal axis. Further, the actions of 3β-Diol are mediated by estrogen receptors, and not androgen receptors, often through a canonical estrogen response element in the promoter of a given target gene. These novel findings compel us to re-evaluate the interpretation of past studies and the design of future experiments aimed at elucidating the specific effects of androgen receptor signaling pathways.

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“…Despite the relatively low homology in the ligand binding domain, the binding characteristics for 17␤-estradiol at the two estrogen receptors are remarkably similar (Kuiper et al 1997). Multiple splice variant isoforms exist for both ER␣ (seven and counting) and ER␤ (five and counting) (Chu and Fuller 1997;Hopp and Fuqua 1998;Maruyama et al 1998;Price et al 2000) These splice variants have largely been observed in transformed cells and in the ER␣ knockout (ERKO␣), ER␤ knockout (ERKO␤), or in the ER␣/ER␤ double knockout animals. It remains to be determined what role these splice variants play in the brain.…”

Section: Estrogen Mechanisms In the Brainmentioning

confidence: 99%

Cellular and Molecular Mechanisms of Estrogen Regulation of Memory Function and Neuroprotection Against Alzheimer's Disease: Recent Insights and Remaining Challenges

Brinton¹

2001

Learn. Mem.

164

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This review focuses on recent advances in our knowledge of estrogen action in the brain. The greatest amount of attention was devoted to those studies that impact our understanding of estrogen regulation of memory function and prevention of degenerative diseases associated with memory systems, such as Alzheimer's disease. A review of recent advances in our understanding of estrogen receptors, both nuclear and membrane, is also presented. Finally, these data are considered in regard to their relevancy to the use of estrogen replacement therapy for cognitive health throughout menopause and the development of an estrogen replacement therapy designed for the unique requirements of the brain.The relationship between memory function and estrogen was first noted clinically as women entering menopause frequently voiced complaints of memory and concentration difficulties (Sherwin 1999). In fact, changes in cognitive functioning have long been associated with menopause (Neurgaren and Kraines 1965). The shift from observation of this phenomenon to scientific human study occurred in the mid-1980's when Sherwin and colleagues began a systematic analysis of the impact of estrogen loss and replacement on memory function (Sherwin 2000). Results of these analyses demonstrated that verbal memory declined with the loss of estrogen and was restored to premenopausal levels when estrogen replacement therapy was instituted immediately following menopause (Sherwin 1988). An earlier important discovery relevant to estrogen effects on memory function came from basic sciences studies in the mid and late 1970's by Luine and colleagues, who found that 17␤-estradiol increased choline acetyltransferase activity which led to increased acetylcholine levels (Luine 1985). Based on these findings, Fillit investigated the impact of estrogen replacement therapy on cognitive function in women with Alzheimer's disease (Fillit et al. 1986). The results of this small clinical trial proved to be pivotal and led to multiple international clinical and epidemiological studies which in turn led to an intense study of the impact of estrogen on the mechanisms of memory in both animals and humans (Brinton 1998). Presented here is a review of the more recent studies, with an emphasis on conceptually linking the many individual findings that have been generated in the past several years. In addition, an analysis of emerging data relevant to our understanding of estrogen regulation of memory function and prevention of Alzheimer's disease is presented. Estrogen-Induced Neurotrophism and Underlying MechanismsEstrogen-induced neurotrophic effects are now well documented in vitro and also in vivo preparations (Fig. 1) (ToranAllerand 1984(ToranAllerand , 2000 Brinton 1993;Murphy and Segal 1996;Brinton et al. 1997bWoolley, 1999). Investigations to determine the mechanism of estrogen-induced neurotrophism have pointed to a temporal cascade of estrogen-inducible effects that are mediated by separate but potentially interacting pathways. It also appears that blockade of ...

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Differential expression of estrogen receptor beta splice variants in rat brain: identification and characterization of a novel variant missing exon 4

Cited by 83 publications

References 34 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

An alternate pathway for androgen regulation of brain function: Activation of estrogen receptor beta by the metabolite of dihydrotestosterone, 5α-androstane-3β,17β-diol

Cellular and Molecular Mechanisms of Estrogen Regulation of Memory Function and Neuroprotection Against Alzheimer's Disease: Recent Insights and Remaining Challenges

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