Neurotransmitters activate the human estrogen receptor in a neuroblastoma cell line

doi:10.1016/S0960-0760(97)00003-4

The Journal of Steroid Biochemistry and Molecular Biology

Volume 61, Issues 1–2, April 1997, Pages 1-9

https://doi.org/10.1016/S0960-0760(97)00003-4 Get rights and content

Abstract

The human neuroblastoma cell line SK-N-SH has been used as a model system to study the interactions of the human estrogen receptor (hER) with neurotransmitters. We have successfully transfected these cells using an adenoviral delivery system and have reconstituted ligand-dependent responses to estradiol and ligand-independent responses to a series of dopamine D1 receptor agonists. The full agonist for the D1 receptor, SKF 82958, shows a robust activation of hER, comparable to that induced by estradiol. This activation is blocked by the protein kinase A inhibitor H-89, is mimicked by forskolin, and is therefore thought to be mediated in part through the cAMP/protein kinase A pathway. We have examined deletion mutants of hER for activation by SKF 82958 and find that both its transactivation domains, AF-1 and AF-2, must cooperate to impact the full response to the agonist. Significantly, an agonist of the muscarinic acetylcholine receptor, carbachol, though not active by itself, synergistically activates hER in conjunction with suboptimal doses of SKF 82958. This is the first reported instance of two neurotransmitters synergizing to activate a member of the nuclear receptor superfamily, and might predict a role for multiple neural inputs modulating the effects of these receptors in the central nervous system.

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Dopamine plays important roles in implicit memory and motivation of behavior. Environmental inputs can produce transgenerational epigenetic changes. This concept also includes the uterus: experimentally, we sought to create hyper-dopaminergic uterine conditions through ineffective dopamine-transporter (DAT) protein, obtained by inserting a stop-codon into the SLC6A3 gene. By crossing WT-dam with KO-sire (or vice-versa), we obtained a 100% DAT-heterozygous (HET) offspring with known derivation of the wild allele: MAT rats are offspring of WT-female and KO-male; PAT rats are offspring of KO-female and WT-male. We reconstructed inheritance of alleles, by crossing PAT-male with MAT-female or vice-versa, obtaining GIX (PAT-male with MAT-female) and DIX (MAT-male with PAT-female) rats (such offspring present specular paths in allele inheritance from grandparents). We conducted three experiments: first, we assessed maternal behaviour (four epigenotypes: WT, MAT, PAT and WHZ=HET-pups fostered-to-a WT-dam); in the second, we analysed sleep-wake cycles of GIX and DIX epigenotypes with their WIT siblings as controls; in the third, we explored the impact of WT or MAT mother on WT or HET pups. MAT-dams (with GIX-pups) express excessive licking/grooming. However, in the mere presence of “sick” epigenotype, PAT-dams (with DIX-pups) and also WHZ (i.e., WT-dams but with HET-pups) expressed greater nest-building care towards the offspring, compared to “true-wild” litters (WT-dams with WT-pups). In Exp. 2 at adolescence, GIX epigenotype showed locomotor hyperactivity during late waking-phase, while DIX epigenotype exhibited pronounced hypoactivity compared to controls. In Exp. 3, we confirmed that HET adolescent pups receiving cares from a MAT-dam may develop additional hyperactivity when awake, but additional hypoactivity during rest-hours. Thus, behavioral changes observed in DAT-heterozygous offspring have opposite courses based on of DAT-allele inheritance from a grandparent through the sire or the dam. In conclusion, behavioural changes in the offspring have antithetic courses with respect to inheritance of DAT-allele via sperm or egg.
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While many physiological effects of estrogens (E) are due to regulation of gene transcription by liganded estrogen receptors (ERs), several effects are also mediated, at least in part, by rapid non-genomic actions of E. Though the relative importance of rapid versus genomic effects in the central nervous system is controversial, we showed previously that membrane-limited effects of E, initiated by an estradiol bovine serum albumin conjugate (E2-BSA), could potentiate transcriptional effects of 17β-estradiol from an estrogen response element (ERE)-reporter in neuroblastoma cells. Here, using specific inhibitors and activators in a pharmacological approach, we show that activation of phosphatidylinositol-3-phosphate kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways, dependent on a Gα_q coupled receptor signaling are important in this transcriptional potentiation. We further demonstrate, using ERα phospho-deficient mutants, that E2-BSA mediated phosphorylation of ERα is one mechanism to potentiate transcription from an ERE reporter construct. This study provides a possible mechanism by which signaling from the membrane is coupled to transcription in the nucleus, providing an integrated view of hormone signaling in the brain.
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In the absence of estradiol, it is likely that OTR expression in MPOA is not at maximal levels, since estradiol activates OTR expression in MPOA [27]. Perhaps, as suggested by Chamapagne et al. [27], D1 agonists activate the ER in a ligand-independent manner [50] so that the expression of OTR in MPOA is increased in spite of the lack of estradiol administration. Another possibility along these lines also exists: the OTR gene contains a CRE and therefore a D1/cAMP/PKA cascade may substitute for estradiol to activate OTR expression [6,7,59].
The medial preoptic area (MPOA) and dopamine (DA) neural systems interact to regulate maternal behavior in rats. Two DA systems are involved: the mesolimbic DA system and the incerto-hypothalamic DA system. The hormonally primed MPOA regulates the appetitive aspects of maternal behavior by activating mesolimbic DA input to the shell region of the nucleus accumbens (NAs). DA action on MPOA via the incerto-hypothalamic system may interact with steroid and peptide hormone effects so that MPOA output to the mesolimbic DA system is facilitated. Neural oxytocin facilitates the onset of maternal behavior by actions at critical nodes in this circuitry. DA–D1 receptor agonist action on either the MPOA or NAs can substitute for the effects of estradiol in stimulating the onset of maternal behavior, suggesting an overlap in underlying cellular mechanisms between estradiol and DA. Maternal memory involves the neural plasticity effects of mesolimbic DA activity. Finally, early life stressors may affect the development of MPOA–DA interactions and maternal behavior.
Structure-function relationship of estrogen receptor α and β: Impact on human health
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17β-Estradiol (E2) controls many aspects of human physiology, including development, reproduction and homeostasis, through regulation of the transcriptional activity of its cognate receptors (ERs). The crystal structures of ERs with agonists and antagonists and the use of transgenic animals have revealed much about how hormone binding influences ER conformation(s) and how this conformation(s), in turn, influences the interaction of ERs with co-activators or co-repressors and hence determines ER binding to DNA and cellular outcomes. This information has helped to shed light on the connection between E2 and the development or progression of numerous diseases. Current therapeutic strategy in the treatment of E2-related pathologies relies on the modulation of ER trancriptional activity by anti-estrogens; however, data accumulated during the last five years reveal that ER activities are not only restricted to the nucleus. ERs are very mobile proteins continuously shuttling between protein targets located within various cellular compartments (e.g., membrane, nucleus). This allows E2 to generate different and synergic signal transduction pathways (i.e., non-genomic and genomic) which provide plasticity for cell response to E2. Understanding the structural basis and the molecular mechanisms by which ER transduce E2 signals in target cells will allow to create new pharmacologic therapies aimed at the treatment of a variety of human diseases affecting the cardiovascular system, the reproductive system, the skeletal system, the nervous system, the mammary gland, and many others.
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Mutation of the AF-2 domain (D538A/E542A/D545A) in the ERα-3× mutant reduced the ability of E2 and SKF to stimulate ER activity by ∼64 and ∼78%, respectively, suggesting that the carboxyl-terminal AF-2 domain contributes to both mechanisms of activation (Fig.6B). An ER mutant lacking the ligand binding and F domains (N282G) was not activated by SKF-82958 or E2 treatment, and this is in agreement with previous studies in SK-N-SH neuroblastoma cells in which the carboxyl terminus of ERα was required for SKF-82958 activation of target gene expression (37). Deletion of the amino-terminal AF-1 domain reduced E2-dependent transcriptional activity by ∼62% and SKF-dependent gene expression by ∼70% in the ERα-179C mutant in comparison to wild type receptor, whereas deletion of the A/B domain in conjunction with the 3× mutation yielded an ER mutant (ERα-179C-3×) unable to activate gene expression in comparison to the empty parent vector.
The transcriptional activity of estrogen receptors (ERs) can be regulated by ligands as well as agents such as dopamine, which stimulate intracellular signaling pathways able to communicate with these receptors. We examined the ability of SKF-82958 (SKF), a previously characterized full dopamine D1 receptor agonist, to stimulate the transcriptional activity of ERα and ERβ. Treatment of HeLa cells with SKF-82958 stimulated robust ERα-dependent transcription from an estrogen-response element-E1b-CAT reporter in the absence of estrogen, and this was accompanied by increased receptor phosphorylation. However, induction of ERβ-directed gene expression under the same conditions was negligible. In our cell model, SKF treatment did not elevate cAMP levels nor enhance transcription from a cAMP-response element-linked reporter. Control studies revealed that SKF-82958, but not dopamine, competes with 17β-estradiol for binding to ERα or ERβ with comparable relative binding affinities. Therefore, SKF-82958 is an ERα-selective agonist. Transcriptional activation of ERα by SKF was more potent than expected from its relative binding activity, and further examination revealed that this synthetic compound induced expression of an AP-1 target gene in a tetradecanoylphorbol-13-acetate-response element (TRE)-dependent manner. A putative TRE site upstream of the estrogen-response element and the amino-terminal domain of the receptor contributed to, but were not required for, SKF-induced expression of an ERα-dependent reporter gene. Overexpression of the AP-1 protein c-Jun, but not c-Fos, strongly enhanced SKF-induced ERα target gene expression but only when the TRE was present. These studies provide information on the ability of a ligand that weakly stimulates ERα to yield strong stimulation of ERα-dependent gene expression through cross-talk with other intracellular signaling pathways producing a robust combinatorial response within the cell.
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Neurotransmitters activate the human estrogen receptor in a neuroblastoma cell line

Abstract

Exp. Gerontol.

Trends Pharmacol. Sci.

J. Steroid Biochem.

Psychoneuroendocrinology

Lancet II

J. Biol. Chem.

Gene

Eur. J. Pharmacol.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Neuropharmacology

Life Sci.

Brain Res.

Pharmacol. Biochem. Behav.

Physiol. Behav.

Cell

Recent Progr. Horm. Res.

Regulation of dendritic spine density in cultured rat hippocampal neurons by steroid hormones

J. Neurosci.

Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons

J. Neurosci.

Estradiol selectively regulates agonist binding sites of the N-methyl-D-aspartate receptor complex in the CA1 region of the hippocampus

Endocrinology

Glutamic acid decarboxylase messenger ribonucleic acid is regulated by estradiol and progesterone in the hippocampus

Endocrinology

Oestrogen and mental state

Nature

Gonadal steroids and astroglial plasticity

Cell. Molec. Neurobiol.

Molecular mechanisms of action of steroid/thyroid receptor superfamily members

Annu. Rev. Biochem.

Regulation of progesterone receptor-mediated transcription by phosphorylation

Science

Dopaminergic and ligand-independent activation of the steroid hormone receptor superfamily

Science

Ligand occupancy is not required for vitamin D receptor and retinoid receptor-mediated transcriptional activation

Molec. Endocr.

Stimulation of estrogen receptor-mediated transcription and alteration in the phosphorylation state of the rat uterine estrogen receptor by estrogen, cyclic adenosine monophosphate and insulin-like growth factor — I

Molec. Endocr.

Peptide growth factors elicit estrogen receptor-dependent transcriptional activation of an estrogen-responsive element

Molec. Endocr.

Peptide growth factor cross-talk with the estrogen receptor requires the AB domain and occurs independently of protein kinase C or estradiol

Endocrinology

Insulin-like growth factors activate estrogen receptor to control the growth and differentiation of the human neuroblastoma cell line SK-ER3

Molec. Endocr.

Peptide growth factor cross-talk with the estrogen receptor requires the $A B$ domain and occurs independently of protein kinase C or estradiol