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Review
. 2009 Aug;30(3):315-27.
doi: 10.1016/j.yfrne.2009.04.011. Epub 2009 May 4.

Membrane estradiol signaling in the brain

Paul Micevych  1 , Reymundo Dominguez
Affiliations
Review

Membrane estradiol signaling in the brain

Paul Micevych et al. Front Neuroendocrinol. 2009 Aug.

Abstract

While the physiology of membrane-initiated estradiol signaling in the nervous system has remained elusive, a great deal of progress has been made toward understanding the activation of cell signaling. Membrane-initiated estradiol signaling activates G proteins and their downstream cascades, but the identity of membrane receptors and the proximal signaling mechanism(s) have been more difficult to elucidate. Mounting evidence suggests that classical intracellular estrogen receptor-alpha (ERalpha) and ERbeta are trafficked to the membrane to mediate estradiol cell signaling. Moreover, an interaction of membrane ERalpha and ERbeta with metabotropic glutamate receptors has been identified that explains the pleomorphic actions of membrane-initiated estradiol signaling. This review focuses on the mechanism of actions initiated by membrane estradiol receptors and discusses the role of scaffold proteins and signaling cascades involved in the regulation of nociception, sexual receptivity and the synthesis of neuroprogesterone, an important component in the central nervous system signaling.

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Figures

Figure 1
Figure 1. E-6-BSA-FITC and E-6-biotin are internalized in primary cortical neurons
(A) Ligand bound receptors are internalized and transported to endosomes to be sorted for recycling or degradation by a β-arrestin mediated mechanism. (B) Cortical neuronal cultures were prepared on glass coverslips and treated with 1 μg/ml E-6-BSA-FITC for 60 min at 37 °C, fixed, and prepared for confocal microscopy. Analysis of reconstructed confocal z-stack slices (side panels) show that E-6-BSA-FITC binding was localized on plasma membranes (arrowheads) and within subcellular compartments (arrows) in several neuronal profiles. (C) Cortical neurons were prepared as described above but were treated with 50 nM E-6-biotin and permeablized after fixation. Biotin conjugated-estradiol was labeled with 1 mg/ml Alexa488-strepavidin to visualize internalization of the ligand. Reconstructed confocal z-stack slices (side panels) demonstrate that the fluorescein labeled E-6-biotin/strepavidin complex was internalized in a similar manner as E-6-BSA-FITC in several neuronal profiles. These findings suggest ligand bound ERs are internalized. Scale bar = 20 μm. [these data redrawn from 42]
Figure 2
Figure 2. Estradiol treatment increased the interaction between ERα and β-arrestin-1 in cortical neuronal cultures
Cortical neuronal cultures were treated with 10 nM estradiol for the times indicated and collected. An antibody raised against the C-terminal of ERα (MC-20) was used to immunoprecipitate (IP) receptors from cellular extracts. To determine the levels of co-immunoprecipitated β-arrestin-1 western immunoblot (IB) analysis (upper panel) was used. The bar graph shows that estradiol treatment increased the interaction between β-arrestin-1 and ERα over time (n = 4). Immunoblot analysis of ERα was used to verify loading. (Tukey's post hoc test, *p < 0.05) [these data redrawn from 42]
Figure 3
Figure 3. Regulation of sexual receptivity through the arcuate-medial preoptic nucleus projection
Estradiol acts in the arcuate nucleus of the hypothalamus (ARH) to activate NPY expression cells. This membrane initiated estradiol signaling requires the interaction of ERα with mGluR1a to phosphorylate PKCθ. NPY released within the ARH activates NPY-Y1 receptors on β-END neurons that project to the medial preoptic nucleus (MPN) where released β-END activates MOR. This circuit enhances the lordosis behavior of the rat.
Figure 4
Figure 4. Proposed mechanism through which estradiol signaling in astrocytes is integrated with local neuronal activity involved in the synthesis of neuroprogesterone
Estradiol (E2), typically of ovarian origin, binds to membrane ERα and activates mGluR1a. This increases levels of free cytoplasmic calcium (Ca2+) through the inositol trisphosphate (IP3) receptor mediated release of intracellular stores of calcium. Elevated levels of intracellular Ca2+ are needed for neuroprogesterone (P4) synthesis in astrocytes. Studies in vitro demonstrate that E2 alone or an agonist mGluR1a alone increase intracellular calcium levels. However, when both an mGluR1a agonist and E2 are applied to astrocytes, the resulting Ca2+ flux is significantly greater, suggesting that P4 synthesis is also augmented. We propose that in vivo when E2-stimulated astrocytes are in the proximity of active nerve terminals, the released glutamate (Glu) activates astrocyte mGluR1a, resulting in significantly greater Ca2+ responses. This elevated Ca2+ response is hypothesized to produce a greater P4 synthesis in astrocytes [113].
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References

    1. Abraham IM, Todman MG, Korach KS, Herbison AE. Critical in vivo roles for classical estrogen receptors in rapid estrogen actions on intracellular signaling in mouse brain. Endocrinology. 2004;145:3055–3061. - PubMed
    1. Acconcia F, Ascenzi P, Bocedi A, Spisni E, Tomasi V, Trentalance A, Visca P, Marino M. Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol. Mol Biol Cell. 2005;16:231–237. - PMC - PubMed
    1. Adams MM, Fink SE, Shah RA, Janssen WG, Hayashi S, Milner TA, McEwen BS, Morrison JH. Estrogen and aging affect the subcellular distribution of estrogen receptor-alpha in the hippocampus of female rats. J Neurosci. 2002;22:3608–3614. - PMC - PubMed
    1. Al-Chaer ED, Traub RJ. Biological basis of visceral pain: recent developments. Pain. 2002;96:221–225. - PubMed
    1. Alarid ET, Bakopoulos N, Solodin N. Proteasome-mediated proteolysis of estrogen receptor: a novel component in autologous down-regulation. Mol Endocrinol. 1999;13:1522–1534. - PubMed

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