Estrogen Modulation of G-protein-coupled Receptors

doi:10.1016/S1043-2760(99)00190-3

Trends in Endocrinology & Metabolism

Volume 10, Issue 9, 1 November 1999, Pages 369-374

https://doi.org/10.1016/S1043-2760(99)00190-3 Get rights and content

Abstract

Estrogen exerts long-term effects in almost every cell through regulation of gene transcription. However, it has been known for some time that estrogen can rapidly alter neuronal firing within seconds, indicating that some cellular effects of estrogen could occur via non-genomic mechanisms. G-protein-coupled receptors (GPCRs) are the largest class of membrane-bound receptors, and it appears that many of the rapid effects mediated by estrogen could involve changes in GPCR–effector system coupling in excitable cells within the reproductive axis.

Section snippets

Central Nervous System (CNS)

Classically, the most compelling role for E₂ in the mammal has been its negative and positive feedback actions on the hypothalamic–pituitary axis to regulate the reproductive cycle. In all mammalian species, disruption of the feedback loop by ovariectomy results in rising levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within one or two days. Restoring the feedback loop with doses of exogenous E₂ that mimic the follicular concentrations of E₂ results in a rapid (<20–30

Physiological Importance

Apart from the classic view that E₂ exerts many of its actions via altered gene transcription, there is now compelling evidence for its direct activation of cellular cascades that impinge on GPCRs. There are several actions of E₂ that are important for a normal reproductive cycle in the female. E₂ can directly inhibit hypothalamic GnRH neurons and activate PKA in β-endorphin neurons as part of the negative feedback actions of E₂ (7, 22). In addition, over a longer time course (hours to days) E₂

Conclusions

In this review, we have touched on some of the recent developments surrounding the E₂-mediated modulation of GPCRs in the reproductive axis. GPCRs are the largest class of membrane receptors, and it appears that E₂ can modulate receptor/effector coupling and/or expression of the genes encoding all major classes of GPCRs in this axis. In addition, the literature is replete with evidence for actions of E₂ in a number of other physiological systems (such as the cardiovascular system). The

Acknowledgements

The authors would like to thank Drs D.K. Grandy, C.E. Roselli and O.K. R nnekleiv for their critical comments. The work from the authors' laboratory was supported by PHS grants DA 05158, DA 00192 (RSDA to MJK) and NS 38809.

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Steroid hormones regulate a wide variety of physiological and developmental functions. Traditional steroid hormone signaling acts through nuclear and cytosolic receptors, altering gene transcription and subsequently regulating cellular activity. This is particularly important in hormonally-responsive cancers, where therapies that target classical steroid hormone receptors have become clinical staples in the treatment and management of disease. Much progress has been made in the last decade in detecting novel receptors and elucidating their mechanisms, particularly their rapid signaling effects and subsequent impact on tumorigenesis. Many of these receptors are membrane-bound and lack DNA-binding sites, functionally separating them from their classical cytosolic receptor counterparts. Membrane-bound receptors have been implicated in a number of pathways that disrupt the cell cycle and impact tumorigenesis. Among these are pathways that involve phospholipase D, phospholipase C, and phosphoinositide-3 kinase. The crosstalk between these pathways has been shown to affect apoptosis and proliferation in cardiac cells, osteoblasts, and chondrocytes as well as cancer cells. This review focuses on rapid signaling by 17β-estradiol and 1α,25-dihydroxy vitamin D3 to examine the integrated actions of classical and rapid steroid signaling pathways both in contrast to each other and in concert with other rapid signaling pathways. This new approach lends insight into rapid signaling by steroid hormones and its potential for use in targeted drug therapies that maximize the benefits of traditional steroid hormone-directed therapies while mitigating their less desirable effects.
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Citation Excerpt :
Palmitoylation of mERs and associations with caveolins allow these receptors to associate with cell membranes, but does not explain the effects of binding at these mERs on neuronal transmission. The rapid effects of estrogens have been shown to be sensitive to G protein manipulation, which suggests that mERα and mERβ may be able to alter G protein receptor activity (Kelly and Wagner, 1999). Research suggests that binding at mERα and mERβ stimulates metabotropic glutamate receptors (mGluRs; Meitzen and Mermelstein, 2011).
This article is part of a Special Issue “Estradiol and cognition”.
Over the past 30 years, research has demonstrated that estrogens not only are important for female reproduction, but also 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.
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17β-Estradiol (E₂) acts in the brain via genomic and non-genomic mechanisms to influence physiology and behavior. There is seasonal plasticity in the mechanisms by which E₂ activates aggression, and non-genomic mechanisms appear to predominate during the non-breeding season. Male song sparrows (Melospiza melodia) display E₂-dependent territorial aggression throughout the year. Field studies show that song sparrow aggression during a territorial intrusion is similar in the non-breeding and breeding seasons, but aggression after an intrusion ends differs seasonally. Non-breeding males stop behaving aggressively within minutes whereas breeding males remain aggressive for hours. We hypothesize that this seasonal plasticity in the persistence of aggression relates to seasonal plasticity in E₂ signaling. We used a non-invasive route of E₂ administration to compare the non-genomic (within 20 min) effects of E₂ on aggressive behavior in captive non-breeding and breeding season males. E₂ rapidly increased barrier contacts (attacks) during an intrusion by 173% in non-breeding season males only. Given that these effects were observed within 20 min of E₂ administration, they likely occurred via a non-genomic mechanism of action. The present data, taken together with past work, suggest that environmental cues associated with the non-breeding season influence the molecular mechanisms through which E₂ influences behavior. In song sparrows, transient expression of aggressive behavior during the non-breeding season is highly adaptive: it minimizes energy expenditure and maximizes the amount of time available for foraging. In all, these data suggest the intriguing possibility that aggression in the non-breeding season may be activated by a non-genomic E₂ mechanism due to the fitness benefits associated with rapid and transient expression of aggression.
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Trends in Endocrinology & Metabolism

ReviewEstrogen Modulation of G-protein-coupled Receptors

Abstract

Section snippets

Central Nervous System (CNS)

Physiological Importance

Conclusions

Acknowledgements

Brain Res.

Brain Res. Bull.

Recent Prog. Horm. Res.

J. Steroid Biochem. Mol. Biol.

Neurosci. Lett.

Horm. Behav.

Neuroscience

Mol. Cell. Endocrinol.

Front. Neuroendocrinol.

Steroids

J. Biol. Chem.

Eur. J. Pharmacol.

Estrogen-induced protein. Time course of synthesis

Biochemistry

The effects of microelectrophoretically applied estrogen, cortisol and acetylcholine on medial preoptic-septal unit activity throughout the estrous cycle of the female rat

Exp. Brain Res.

The specificity of the response of preoptic-septal area neurons to estrogen: 17α-estradiol versus 17β-estradiol and the response of extrahypothalamic neurons

Exp. Brain Res.

Electrical effects of steroids in neurons

Estrogen: nontranscriptional signaling pathway

Recent Prog. Horm. Res.

Nontranscriptional effects of estradiol in neuropeptide neurons

Curr. Opin. Endocrinol. Metab.

Factors influencing the positive feedback action of estrogen upon luteinizing hormone surge in the ovariectomized guinea pig

Endocrinology

The negative feedback control by estradiol and progesterone of LH secretion in the ovariectomized rhesus monkey

Endocrinology

In vivo gonadotropin-releasing hormone release and serum luteinizing hormone measurements in ovariectomized, estrogen-treated Rhesus macaques

Endocrinology

Feedback effects of estradiol and progesterone upon gonadotropin and prolactin release

Obstet. Gynecol.

Acute effects of intravenous infusion of 17-beta-estradiol on gonadotropin release in pre- and post-menopausal women

J. Clin. Endocrinol. Metab.

Hyperpolarization of hypothalamic parvocellular neurons by 17β-estradiol and their identification through intracellular staining with procion yellow

Exp. Brain Res.

Mechanism of the rapid effect of 17β-estradiol on medial amygdala neurons

Science

Estrogen rapidly attenuates a GABAB response in hypothalamic neurons

Neuroendocrinology

Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor

J. Neurosci.

Infundibular gonadotropin-releasing hormone neurons are inhibited by direct opioid and autoregulatory synapses in juvenile monkeys

Neuroendocrinology

β-Endorphin and gonadotropin-releasing hormone synaptic input to gonadotropin-releasing hormone neurosecretory cells in the male rat

J. Comp. Neurol.

Review
Estrogen Modulation of G-protein-coupled Receptors