Membrane-initiated estrogen signaling in hypothalamic neurons

doi:10.1016/j.mce.2008.04.014

Molecular and Cellular Endocrinology

Volume 290, Issues 1–2, 13 August 2008, Pages 14-23

https://doi.org/10.1016/j.mce.2008.04.014 Get rights and content

Abstract

It is well known that many of the actions of 17β-estradiol (E2) in the central nervous system are mediated via intracellular receptor/transcription factors that interact with steroid response elements on target genes. However, there is compelling evidence for membrane steroid receptors for estrogen in hypothalamic and other brain neurons. But it is not well understood how estrogen signals 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 E2 can rapidly alter neuronal activity within seconds, indicating that some cellular effects can occur via membrane delimited events. In addition, E2 can affect second messenger systems including calcium mobilization and a plethora of kinases to alter cell signaling. Therefore, this review will consider our current knowledge of rapid membrane-initiated and intracellular signaling by E2 in the hypothalamus, the nature of receptors involved and how they contribute to homeostatic functions.

Section snippets

Nuclear-initiated signaling of E2

Estrogen receptors regulate cellular function through at least two signaling pathways previously broadly classified as “genomic” versus “nongenomic” (McEwen and Alves, 1999, Björnström and Sjöberg, 2005). However, recently the FASEB steroid signaling work group suggested that “membrane-initiated steroid signaling” and “nuclear-initiated steroid signaling” are more appropriate terminologies (Hammes and Levin, 2007). The nuclear-initiated signaling of estrogen via ERα and ERβ exert diverse

Membrane-initiated signaling of E2

It has been known for a number of years that estrogen has acute, membrane-initiated signaling actions in the brain (for review see Kelly and Rønnekleiv, 2002, Rønnekleiv and Kelly, 2005, Bryant et al., 2006). The nature and significance of these actions have been a matter of dispute. However, it is now widely accepted that some of the actions of estrogen are quite rapid and cannot be attributed to the classical nuclear-initiated steroid signaling of ERα or ERβ. One view is that both nuclear and

17β-Estradiol, growth factors and reproduction

Systemic administration of E2 in ovariectomized rats activates IGF-I receptors and induces the association between IGF-I receptors and ERα in the hypothalamus (Quesada and Etgen, 2001, Cardona-Gómez et al., 2002, Mendez et al., 2003). Similar to the effects in cortical neurons, there is an interaction (complex formation) between the p85 subunit of PI3K and ERα within 1–3 h, which leads to activation of Akt (Cardona-Gómez et al., 2002, Mendez et al., 2003). Also, the E2-induced activation of

17β-Estradiol and GnRH neurosecretion

Despite having been studied extensively for over 25 years, the mechanism(s) by which estrogen regulates gonadotropin releasing hormone (GnRH) neurons is not well understood. It has been obvious for a number of years that GnRH neurons are modulated by estrogen in a complex manner. For example, loss of estrogen by ovariectomy disrupts GnRH regulation of pituitary LH secretion and results in elevated levels of plasma LH. This effect is due to the loss of negative feedback actions of E2. However,

Effects of 17β-estradiol on VMH and arcuate neurons: role in regulation of feeding

In addition to its role in the control of reproduction, estrogen is involved in the regulation of appetite, energy expenditure, body weight, adipose tissue deposition and distribution in females (Milewicz et al., 2000, Geary, 2001, Poehlman, 2002). Ovariectomy induces an increase in food intake and decreases ambulatory and wheel running activities in rodents, all of which are reversed with estrogen replacement (Ahdieh and Wade, 1982, Colvin and Sawyer, 1969, Shimomura et al., 1990, Asarian and

Cross-talk between membrane actions and genome activation

The gonadal steroid E2 participates in numerous functions including reproduction, feeding, neuroprotection and cognition. It has been known for some time that the main actions of E2 is to regulate gene transcription through binding to and activating nuclear receptors that can stimulate or inhibit gene transcription at specific DNA binding sites. However, recently it has become clear that E2 can exert its action through multiple signaling mechanisms including membrane-initiated, cytoplasmic as

Acknowledgments

The authors thank members of their laboratories who contributed to the work described herein, especially Dr. Jian Qiu, Dr. Chunguang Zhang, Troy A. Roepke, Dr. Anna Malyala and Dr. Ms. Martha A. Bosch. Also, special thanks to Ms. Martha A. Bosch for her skilled assistance with the illustrations and manuscript preparation. The work from the authors’ laboratories was supported by PHS grants NS 43330, NS 38809 and DK 68098.

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ReviewMembrane-initiated estrogen signaling in hypothalamic neurons

Abstract

Section snippets

Nuclear-initiated signaling of E2

Membrane-initiated signaling of E2

17β-Estradiol, growth factors and reproduction

17β-Estradiol and GnRH neurosecretion

Effects of 17β-estradiol on VMH and arcuate neurons: role in regulation of feeding

Cross-talk between membrane actions and genome activation

Acknowledgments

Horm. Behav.

Neuroscience

Brain Res.

Brain Res.

Mol. Brain Res.

Physiol. Behav.

Horm. Behav.

Curr. Opin. Neurobiol.

Horm. Behav.

J. Steroid Biochem. Mol. Biol.

Trends Endocrinol. Metab.

Biochem. Biophys. Res. Commun.

Peptides

Trends Endocrinol. Metab.

Mol. Cell. Endocrinol.

Front. Neuroendocrinol.

Biochem. Biophys. Res Commun.

Trends Endocrinol. Metab.

Brain Res.

Brain Res. Bull.

Steroids

Physiol. Behav.

Mol. Brain Res.

Rapid action of estrogens on intracellular calcium oscillations in primate LHRH-1 neurons

Endocrinology

Firing pattern and rapid modulation of activity by estrogen in primate luteinizing hormone releasing hormone-1 neurons

Endocrinology

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

J. Neurosci.

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

Endocrinology

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

J. Comp. Physiol. Psychol.

Epidermal growth factor activates reproductive behavior independent of ovarian steroids in female rodents

Mol. Endocrinol.

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

Endocrinology

Unit activity in the hypothalamus of the cyclic female rat: effect of genital stimuli and progesterone

J. Endocrinol.

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

Neuroendocrinology

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

Proc. Natl. Acad. Sci. U.S.A.

Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes

Mol. Endocrinol.

Virtual and biomolecular screening converge on a selective agonist for GPR30

Nat. Chem. Biol.

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

J. Neurosci.

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

J. Neurosci.

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

J. Endocrinol.

Multiple pathways transmit neuroprotective effects of gonadal steroids

Endocrine

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

J. Neurosci.

Rapid actions of steroid receptors in cellular signaling pathways

Sci. STKE

Estradiol induces diurnal shifts in GABA transmission to gonadotropin-releasing hormone neurons to provide a neural signal for ovulation

J. Neurosci.

Gonadal hormones determine sensitivity to central leptin and insulin

Diabetes

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

Diabetes

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

Neuroendocrinology

Estrogen modulation of the α1-adrenergic response of hypothalamic neurons

Neuroendocrinology

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

Review
Membrane-initiated estrogen signaling in hypothalamic neurons

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

Estrogen modulation of the α₁-adrenergic response of hypothalamic neurons