Estradiol activates group I and II metabotropic glutamate receptor signaling, leading to opposing influences on cAMP response element-binding protein.

Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 06/2005; 25(20):5066-78. DOI: 10.1523/JNEUROSCI.1427-05.2005
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The estrogen receptor and glucocorticoid receptor are members of the nuclear receptor superfamily that can signal using both non-genomic and genomic transcriptional modes. Though genomic modes of signaling have been well characterized and several behaviors attributed to this signaling mechanism, the physiological significance of non-genomic modes of signaling has not been well understood. This has partly been due to the controversy regarding the identity of the membrane ER (mER) or membrane GR (mGR) that may mediate rapid, non-genomic signaling and the downstream signaling cascades that may result as a consequence of steroid ligands binding the mER or the mGR. Both estrogens and glucocorticoids exert a number of actions on the hypothalamus, including feedback. This review focuses on the various candidates for the mER or mGR in the hypothalamus and the contribution of non-genomic signaling to classical hypothalamically driven behaviors and changes in neuronal morphology. It also attempts to categorize some of the possible functions of non-genomic signaling at both the cellular level and at the organismal level that are relevant for behavior, including some behaviors that are regulated by both estrogens and glucocorticoids in a potentially synergistic manner. Lastly, it attempts to show that steroid signaling via non-genomic modes may provide the organism with rapid behavioral responses to stimuli.
    Frontiers in Endocrinology 02/2015; 6:18. DOI:10.3389/fendo.2015.00018
  • [Show abstract] [Hide abstract]
    ABSTRACT: 17β-estradiol (E2), a key participant on the initiation of the LH surge, exerts both positive and negative feedback on GnRH neurons. We sought to investigate potential interactions between estrogen receptors alpha (ERα) and beta (ERβ) and gonadotropin releasing hormone receptor (GnRH-R) in GT1-7 cells. Radioligand binding studies demonstrated a significant decrease in saturation E2 binding in cells treated with GnRH agonist. Conversely, there was a significant reduction in GnRH binding in GT1-7 cells treated with E2. In BRET(1) experiments, ERα-ERα dimerization was suppressed in GT1-7 cells treated with GnRH agonist (p<0.05). There was no evidence of direct interaction between ERs and GnRH-R. This study provides the first evidence of reduced ERα homodimerization by GnRH agonist. Collectively, these findings demonstrate significant cross-talk between membrane-initiated GnRH and E2 signaling in GT1-7 cells. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Molecular and Cellular Endocrinology 01/2015; 404. DOI:10.1016/j.mce.2015.01.023 · 4.24 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Posttraumatic stress disorder (PTSD) is a psychiatric illness whose prevalence in women is more than twice the rate as men. Despite a burgeoning literature characterizing sex differences in PTSD incidence and its disproportionate burden on society, there is a dearth of literature describing biological mechanisms underlying these disparities. However, the recent identification of biomarkers of PTSD by translational neuroscientists offers a promising opportunity to explore sex interactions in PTSD phenotypes. A notable observation is that individuals with PTSD show deficits in their ability to inhibit conditioned fear responding after extinction training. Given that extinction procedures, via exposure-based cognitive behavioral therapy, make up one of the predominant modes of treatment in PTSD, there is a critical need for more research on sex interactions in this form of fear regulation. An emerging hypothesis is that fluctuating gonadal hormones, especially estrogen, in the menstrual cycle may play a critical role in fear extinction and, hence, PTSD vulnerability and symptom severity in women. The current review discusses how the study of putative activational effects of estrogen on fear extinction may be harnessed to advance the search for better treatments for PTSD in women. We conclude that estrogen treatment may be a putative pharmacologic adjunct in extinction-based therapies and should be tracked in the menstrual cycle during the course of PTSD treatment. Published by Elsevier Inc.
    Biological Psychiatry 02/2015; DOI:10.1016/j.biopsych.2015.02.007 · 9.47 Impact Factor

Full-text (2 Sources)

Available from
May 23, 2014