Elsevier

Brain Research

Volume 1514, 13 June 2013, Pages 75-82
Brain Research

Research Report
A selective membrane estrogen receptor agonist maintains autonomic functions in hypoestrogenic states

https://doi.org/10.1016/j.brainres.2013.03.020Get rights and content

Abstract

It is well known that many of the actions of estrogens in the central nervous system are mediated via intracellular receptor/transcription factors that interact with steroid response elements on target genes. But there is also a compelling evidence for the involvement of membrane estrogen receptors in hypothalamic and other CNS functions. However, it is not well understood how estrogens signal via membrane receptors, and how these signals impact not only membrane excitability but also gene transcription in neurons. Indeed, it has been known for sometime that estrogens can rapidly alter neuronal activity within seconds, indicating that some cellular effects can occur via membrane delimited events. In addition, estrogens can affect second messenger systems including calcium mobilization and a plethora of kinases within neurons to alter cellular functions. Therefore, this brief review will summarize our current understanding of rapid membrane-initiated and intracellular signaling by estrogens in the hypothalamus, the nature of receptors involved and how these receptors contribute to maintenance of homeostatic functions, many of which go awry in menopausal states.

This article is part of a Special Issue entitled Hormone Therapy.

Section snippets

Membrane-initiated signaling of estrogens

It has been known for a number of years that 17β-estradiol (E2) has acute, membrane-initiated signaling actions in the brain (Kelly and Rønnekleiv, 2002, Rønnekleiv and Kelly, 2005, Micevych and Dominguez, 2009). A decade ago the nature and physiological significance of these actions were a matter of debate, but it is now widely accepted that some of the actions of E2 are quite rapid and cannot be attributed to the classical nuclear-initiated steroid signaling of ERα or ERβ. Importantly, ERα

Membrane-initiated signaling of E2 and hypothalamic control of autonomic functions

Besides its quintessential role in the feedback control of the reproductive axis, E2 modulates a number of hypothalamic-regulated autonomic functions, most notably energy homeostasis and temperature. E2 signaling via ERα is a critical component in the hypothalamic regulation of energy balance (Geary et al., 2001). In rodents, hypo-estrogenic states are clearly associated with decreased activity and an increase in body weight (Czaja and Goy, 1975, Butera and Czaja, 1984, Czaja, 1984, McCaffrey

Summary

It is obvious from the plethora of studies using membrane-delimited E2 ligands and the mER selective ligand STX that “genomic” actions of E2 in the brain do not require the direct nuclear targeting of estrogen receptors (ERα and ERβ). Signals that are initiated by E2 at the plasma membrane can trigger multiple intracellular signaling cascades including activation of MAPK, PI3K, and PKC pathways (Watters et al., 1997, Bi et al., 2001, Cato et al., 2002, Yang et al., 2003, Deisseroth et al., 2003

Acknowledgments

The authors thank current and former members of their laboratories who contributed to the work described herein, especially Drs. Jian Qiu, Troy A. Roepke and Chunguang Zhang and Ms. Martha A. Bosch. Research reported in this publication was supported by the National Institutes Health Grants NS 38809, NS 43330 and DK 68098. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health.

References (119)

  • E.J. Filardo et al.

    GPR30: a seven-transmembrane-spanning estrogen receptor that triggers EGF release

    Trends Endocrinol. Metab.

    (2005)
  • R.R. Freedman et al.

    Estrogen raises the sweating threshold in postmenopausal women with hot flashes

    Fertil. Steril.

    (2002)
  • T. Funakoshi et al.

    G protein-coupled receptor 30 is an estrogen receptor in the plasma membrane

    Biochem. Biophys. Res. Commun.

    (2006)
  • G.Z. Huang et al.

    Estradiol acutely suppresses inhibition in the hippocampus through a sex-specific endocannabinoid and mGluR-dependent mechanism

    Neuron

    (2012)
  • M.J. Kelly et al.

    Rapid membrane effects of estrogen in the central nervous system

  • T.A. McCaffrey et al.

    Diverse effects of estradiol-17 beta: concurrent suppression of appetite, blood pressure and vascular reactivity in conscious, unrestrained animals

    Physiol. Behav.

    (1989)
  • I. Merchenthaler et al.

    The effect of estrogens and antiestrogens in a rat model for hot flush

    Maturitas

    (1998)
  • P. Micevych et al.

    Membrane estradiol signaling in the brain

    Front. Neuroendocrinol.

    (2009)
  • M.L. Moline et al.

    Sleep in women across the life cycle from adulthood through menopause

    Sleep Med. Rev.

    (2003)
  • E.R. Prossnitz et al.

    GPR30: A G protein-coupled receptor for estrogen

    Mol. Cell. Endocrinol.

    (2007)
  • J. Qiu et al.

    Modulation of hypothalamic neuronal activity through a novel G-protein coupled estrogen membrane receptor

    Steroids

    (2008)
  • A.J. Rapkin

    Vasomotor symptoms in menopause: physiologic condition and central nervous system approaches to treatment

    Am. J. Obstet. Gynecol.

    (2007)
  • O.K. Rønnekleiv et al.

    Diversity of ovarian steroid signaling in the hypothalamus

    Front. Neuroendocrinol.

    (2005)
  • H. Shimizu et al.

    Estrogen increases hypothalamic neuropeptide Y (NPY) mRNA expression in ovariectomized obese rat

    Neurosci. Lett.

    (1996)
  • J.W. Simpkins et al.

    Similarities between morphine withdrawal in the rat and the menopausal hot flush

    Life Sci.

    (1983)
  • K. Sipe et al.

    Serotonin 2A receptors modulate tail-skin temperature in two rodent models of estrogen deficiency-related thermoregulatory dysfunction

    Brain Res.

    (2004)
  • V. Stearns et al.

    Hot flushes

    Lancet

    (2002)
  • S. Takeda et al.

    Leptin regulates bone formation via the sympathetic nervous system

    Cell

    (2002)
  • I.M. Abraham et al.

    Estrogen receptor beta mediates rapid estrogen actions on gonadotropin-releasing hormone neurons in vivo

    J. Neurosci.

    (2003)
  • I.M. Abrahám et al.

    Critical in vivo roles for classical estrogen receptors in rapid estrogen actions on intracellular signaling in mouse brain

    Endocrinology

    (2004)
  • H.B. Ahdieh et al.

    Effects of hysterectomy on sexual receptivity, food intake, running wheel activity, and hypothalamic estrogen and progestin receptors in rats

    J. Comp. Physiol. Psychol.

    (1982)
  • S.M. Appleyard et al.

    A role for the endogenous opioid beta-endorphin in energy homeostasis

    Endocrinology

    (2003)
  • C.L. Bethea et al.

    Effects of progesterone on prolactin, hypothalamic beta-endorphin, hypothalamic substance P, and midbrain serotonin in guinea pigs

    Neuroendocrinology

    (1995)
  • R. Bi et al.

    Cyclic changes in estradiol regulate synaptic plasticity through the MAP kinase pathway

    Proc. Natl. Acad. Sci. USA

    (2001)
  • C.G. Bologa et al.

    Virtual and biomolecular screening converge on a selective agonist for GPR30

    Nat. Chem. Biol.

    (2006)
  • G. Bondar et al.

    Estradiol-induced estrogen receptor-α trafficking

    J. Neurosci.

    (2009)
  • J.A. Boulant

    Neuronal basis of Hammel's model for set-point thermoregulation

    J. Appl. Physiol.

    (2006)
  • M.I. Boulware et al.

    Caveolin proteins are essential for distinct effects of membrane estrogen receptors in neurons

    J. Neurosci.

    (2007)
  • M.I. Boulware et al.

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

    J. Neurosci.

    (2005)
  • E. Brailoiu et al.

    Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system

    J. Endocrinol.

    (2007)
  • E.M. Brooks et al.

    Chronic hormone replacement therapy alters thermoregulatory and vasomotor function in postmenopausal women

    J. Appl. Physiol.

    (1997)
  • H.F. Carrer et al.

    Estradiol regulates the slow Ca2+-activated K+ current in hippocampal pyramidal neurons

    J. Neurosci.

    (2003)
  • A.C.B. Cato et al.

    Rapid actions of steroid receptors in cellular signaling pathways

    Science's STKE

    (2002)
  • D.J. Clegg et al.

    Gonadal hormones determine sensitivity to central leptin and insulin

    Diabetes

    (2006)
  • D.J. Clegg et al.

    Estradiol-dependent decrease in the orexigenic potency of ghrelin in female rats

    Diabetes

    (2007)
  • G.B. Colvin et al.

    Induction of running activity by intracerebral implants of estrogen in overiectomized rats

    Neuroendocrinology

    (1969)
  • J.F. Couse et al.

    Estrogen receptor null mice: what have we learned and where will they lead us?

    Endocr. Rev.

    (1999)
  • W.R. Crowley et al.

    Effects of ovarian hormones on the concentrations of immunoreactive neuropeptide Y in discrete brain regions of the female rat: correlation with serum luteinizing hormone (LH) and median eminence LH-releasing hormone

    Endocrinology

    (1985)
  • D.C. Deecher et al.

    Alleviation of thermoregulatory dysfunction with the new serotonin and norepinephrine reuptake inhibitor desvenlafaxine succinate in ovariectomized rodent models

    Endocrinology

    (2007)
  • P. Dewing et al.

    Membrane estrogen receptor-α interactions with metabotropic glutamate receptor 1a modulate female sexual receptivity in rats

    J. Neurosci.

    (2007)
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