Boulware, MI, Weick, JP, Becklund, BR, Kuo, SP, Groth, RD and Mermelstein, PG. Estradiol activates group I and II metabotropic glutamate receptor signaling, leading to opposing influences on cAMP response element-binding protein. J Neurosci 25: 5066-5078

Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2005; 25(20):5066-78. DOI: 10.1523/JNEUROSCI.1427-05.2005
Source: PubMed


In addition to mediating sexual maturation and reproduction through stimulation of classical intracellular receptors that bind DNA and regulate gene expression, estradiol is also thought to influence various brain functions by acting on receptors localized to the neuronal membrane surface. Many intracellular signaling pathways and modulatory proteins are affected by estradiol via this unconventional route, including regulation of the transcription factor cAMP response element-binding protein (CREB). However, the mechanisms by which estradiol acts at the membrane surface are poorly understood. Because both estradiol and CREB have been implicated in regulating learning and memory, we characterized the effects of estradiol on this transcription factor in cultured rat hippocampal neurons. Within minutes of administration, estradiol triggered mitogen-activated protein kinase (MAPK)-dependent CREB phosphorylation in unstimulated neurons. Furthermore, after brief depolarization, estradiol attenuated L-type calcium channel-mediated CREB phosphorylation. Thus, estradiol exhibited both positive and negative influences on CREB activity. These effects of estradiol were sex specific and traced to membrane-localized estrogen receptors that stimulated group I and II metabotropic glutamate receptor (mGluR) signaling. Activation of estrogen receptor alpha (ERalpha) led to mGluR1a signaling, triggering CREB phosphorylation through phospholipase C regulation of MAPK. In addition, estradiol stimulation of ERalpha or ERbeta triggered mGluR2/3 signaling, decreasing L-type calcium channel-mediated CREB phosphorylation. These results not only characterize estradiol regulation of CREB but also provide two putative signaling mechanisms that may account for many of the unexplained observations regarding the influence of estradiol on nervous system function.

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    • "There are other mechanisms involved in ER-membrane associations; multiple proteins including the adapter protein Shc, the calmodulin binding protein Striatin, and the modulator of nongenomic activity of estrogen receptor, have also been implicated in the membrane association of estrogen receptors (Boonyaratanakornkit, 2011; Boonyaratanakornkit and Edwards, 2007). However, the palmitoylation of mER, and mER associations with caveolins and mGluRs, provide the most complete explanation for how mERs become associated with the cell membrane, and occur in dopamine-innervated regions (Boulware et al., 2005; Grove-Strawser et al., 2010; Huang and Woolley, 2012; Meitzen and Mermelstein, 2011). GPER1: a membrane-bound G protein-coupled estrogen receptor "
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    ABSTRACT: Over the past 30 years, research has demonstrated that estrogens are not only important for female reproduction, but play a role in a diverse array of cognitive functions. Originally, estrogens were thought to have only one receptor, localized exclusively to the cytoplasm and nucleus of cells. However, it is now known that there are at least three estrogen receptors (ERs): ERα, ERβ and G-protein coupled ER1 (GPER1). In addition to being localized to nuclei, ERα and ERβ are localized to the cell membrane, and GPER1 is also observed at the cell membrane. The mechanism through which ERs are associated with the membrane remains unclear, but palmitoylation of receptors and associations between ERs and caveolin are implicated in membrane association. ERα and ERβ are mostly observed in the nucleus using light microscopy unless they are particularly abundant. However, electron microscopy has revealed that ERs are also found at the membrane in complimentary distributions in multiple brain regions, many of which are innervated by dopamine inputs and were previously thought to contain few ERs. In particular, membrane-associated ERs are observed in the prefrontal cortex, dorsal striatum, nucleus accumbens, and hippocampus, all of which are involved in learning and memory. These findings provide a mechanism for the rapid effects of estrogens in these regions. The effects of estrogens on dopamine-dependent cognition likely result from binding at both nuclear and membrane-associated ERs, so elucidating the localization of membrane-associated ERs helps provide a more complete understanding of the cognitive effects of these hormones. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · Hormones and Behavior
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    • "2011 ; Grassi et al . , 2012 ) . In the present study we observed a clear and robust striatal E2 - dependent LTP in the male . Although it is possible that a similar phenomenon might occur also in the striatum of female rat , as suggested by previous behavioral studies ( Hampson and Kimura , 1988 ; Becker , 1990a , b ; Mermelstein et al . , 1996 ; Boulware et al . , 2005 ; Olesen et al . , 2005 ) , possible difference of gender sensitivities of striatal neurons to E2 might also occur . It is possible , in fact , that different expression of nuclear and membrane ERs in female vs . males might cause gender differences in the interaction of E2 with DA . However , it appears evident from our study that the e"
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    ABSTRACT: 17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic interneurons (ChIs). Activation of a D1-like DA receptor/cAMP/PKA-dependent pathway restored LTP. In MSNs exogenous E2 reversed the effect of ARO inhibition. Also antagonism of M1 muscarinic receptors prevented the D1-like receptor-mediated restoration of LTP confirming a role for ChIs in controlling the E2-mediated LTP of MSNs. A novel striatal interaction, occurring between ERs and D1-like receptors in both MSNs and ChIs, might be critical to regulate basal ganglia physiology and to compensate synaptic alterations in Parkinson’s disease.
    Full-text · Article · May 2015 · Frontiers in Cellular Neuroscience
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    • "The importance of ERK in mediating the effects of ERα and ERβ in vivo were also consistent with findings from cultured hippocampal primary neurons showing that membrane-localized ERα and ERβ regulate CREB by activating ERK and metabotropic glutamate receptors (mGluRs), including mGluR1a (Boulware et al., 2005). Therefore, we hypothesized that mGluR1a might play a role in the effects of both E 2 and the ER agonists. "
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    ABSTRACT: Since the publication of the 1998 special issue of Hormones and Behavior on estrogens and cognition, substantial progress has been made towards understanding the molecular mechanisms through which 17β-estradiol (E2) regulates hippocampal plasticity and memory. Recent research has demonstrated that rapid effects of E2 on hippocampal cell signaling, epigenetic processes, and local protein synthesis are necessary for E2 to facilitate the consolidation of object recognition and spatial memories in ovariectomized female rodents. These effects appear to be mediated by non-classical actions of the intracellular estrogen receptors ERα and ERβ, and possibly by membrane-bound ERs such as the G-protein-coupled estrogen receptor (GPER). New findings also suggest a key role of hippocampally-synthesized E2 in regulating hippocampal memory formation. The present review discusses these findings in detail and suggests avenues for future study. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · May 2015 · Hormones and Behavior
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