Estrogen Receptor (ER)β Isoforms Rather Than ERα Regulate Corticotropin-Releasing Hormone Promoter Activity through an Alternate Pathway

Miller, W.J.; Suzuki, Shotaro; Miller, Lydia; Handa, Robert J.; Uht, Rosalie Maire

doi:10.1523/jneurosci.5540-03.2004

Cited by 89 publications

(78 citation statements)

References 55 publications

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“…The CRF promoter contains sites at which agonist-bound estrogen receptor complexes can affect transcription (Vamvakopoulos and Chrousos, 1993). More recently, estrogen receptor b-isoforms were found to be colocalized with CRF in a population of paraventricular hypothalamic neurons in rat and to regulate the CRF promoter in transfected cells (Miller et al, 2004). These findings are consistent with the idea that estrogen effects on CRF transcription (effects that are presynaptic to the pituitary) are related to the sexually dimorphic HPA response.…”

Section: Sex Differences In Hpa Vs Lc Sensitivity To Stresssupporting

confidence: 73%

“…This included greater levels of CRF receptor protein in the LC, increased neuronal sensitivity to CRF and differential regulation of CRF-LC interactions by prior stress in female vs male rats. Unlike the sex differences in HPA axis responsivity, which have been attributed to circulating hormones (Burgess and Handa, 1992;Miller et al, 2004;Seale et al, 2004), sex differences in LC sensitivity were independent of adult hormonal status. Given the role of the LC-NE system in arousal and attention (Aston-Jones et al, 2000), the present results predict that the expression of these aspects of the stress response will be enhanced in females.…”

Section: Discussionmentioning

confidence: 73%

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Sexually Dimorphic Responses of the Brain Norepinephrine System to Stress and Corticotropin-Releasing Factor

Curtis

Bethea

Valentino

2005

Neuropsychopharmacol

191

196

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Stress-related psychiatric disorders are more prevalent in females than males, and this has been attributed to differences in stress sensitivity. As activation of the locus coeruleus (LC)-norepinephrine (NE) system is an important component of the stress response, this study compared LC responses to stress in female and male rats under different hormonal conditions in the halothane-anesthetized state. The mean basal LC discharge rate was similar between groups. However, the magnitude of LC activation elicited by hypotensive stress was substantially greater in females, regardless of hormonal status. The difference in stress sensitivity could be attributed to the differential postsynaptic sensitivity of LC neurons to corticotropin-releasing factor (CRF), which mediates LC activation by hypotension. CRF was 10-30 times more potent in activating LC neurons in female vs male rats. Interestingly, previous exposure to swim stress differentially regulated LC responses to CRF by sensitizing LC neurons of male, but not female, rats to CRF. The net effect of this was to abolish sex differences in LC sensitivity. Finally, CRF receptor (CRF-R) protein levels in the LC were greater in ovarectomized female vs male rats. This is the first study to demonstrate sex differences in the stress responsiveness of the brain noradrenergic system. Substantial sex differences were apparent in postsynaptic sensitivity to CRF and stress-induced regulation of postsynaptic sensitivity to CRF. These sex differences in the CRF regulation of the LC-NE system translate to a differential response to stress and may play a role in the increased vulnerability of females to stress-related psychiatric disorders.

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Section: Sex Differences In Hpa Vs Lc Sensitivity To Stresssupporting

confidence: 73%

Section: Discussionmentioning

confidence: 73%

Sexually Dimorphic Responses of the Brain Norepinephrine System to Stress and Corticotropin-Releasing Factor

Curtis

Bethea

Valentino

2005

Neuropsychopharmacol

191

196

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“…Although parallel examples of such ER-dependent differential regulation on other gene expression in hippocampus remain to be developed, different effects of ER isoforms have been reported in endothelial cells and brain hypothalamus. For example, ER␤ but not ER␣ regulated corticotropin-releasing hormone promoter activity (40). In contrast, activation of ER␣ but not ER␤ increased progesterone receptor expression in the developing rat brain (41).…”

Section: E2-regulated Apoe Expression Is Mediated By Er and Is Er Isomentioning

confidence: 92%

Activation of estrogen receptor α increases and estrogen receptor β decreases apolipoprotein E expression in hippocampus in vitro and in vivo

Wang

Irwin

Brinton

2006

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

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Alzheimer's disease ͉ estrogen therapy ͉ risk factor regulation ͉ Alzheimer's disease prevention A polipoprotein E (ApoE) is a 34-kDa lipid binding protein that functions in the transport of triglycerides and cholesterol in multiple tissues, including brain, by interacting with lipoprotein receptors on target cells (1-4). Three ApoE isoforms exist in humans: ApoE2, ApoE3, and ApoE4, which differ from one another by single amino acid substitutions at positions 112 and 158, ApoE2 (Cys-112, Cys-158), ApoE3 (Cys-112, Arg-158), and ApoE4 (Arg-112, Arg-158) (5). Substitution of cysteine at position 158 in ApoE2 results in hypocholesterolemia caused by low levels of low-density lipoprotein (LDL), cholesterol (6). In contrast, substitution of cysteine with arginine at position 112 in ApoE4 results in elevation of plasma cholesterol and LDL levels and predisposes the carrier to cardiovascular disease and neurodegenerative disorders, including Alzheimer's disease (AD) (7,8).Statistically, individuals with one copy of the ApoE4 allele show a 4-fold increase in the risk of AD, whereas those with two copies of the ApoE4 allele exhibit a 15-fold increase in risk coupled with a significantly lower age of onset compared with AD patients carrying ApoE2͞3 alleles (9). The ApoE4 allele itself appears to account for as much as 50% of the populationattributable AD risk in the United States (for reviews see refs. 10 and 11). Thus, ApoE4 is considered a risk factor for late-onset AD, whereas ApoE2 and ApoE3 are associated with decreased risk of AD (10,12,13).Previous in vitro and in vivo analyses indicate that 17␤-estradiol (E 2 ) increased ApoE expression in astrocytes and microglia and in neurons (14, 15). Further, ApoE synthesis was required for E 2 -induced neuroprotection and neurotrophism, including neurite outgrowth (16,17).Recently, we discovered that in HT-22 cells ectopically transfected with full-length estrogen receptor (ER) (ER␣ or ER␤), E 2 -induced an opposite effect on ApoE expression depending on the transfected ER subtype. Based on our own data and others (17-19), we hypothesized that ApoE expression is differentially regulated by ER subtypes. To test this hypothesis, we investigated the impact of ER␣ versus ER␤ on ApoE gene expression by using real-time RT-PCR with confirmation of protein levels by Western blot in primary cultured rat hippocampal neurons. To determine the in vivo significance of our in vitro findings, we conducted in vivo analyses in ovariectomized (OVX) female rats treated with either the ER␣-selective ligand, propylpyrazole triol (PPT) or the ER␤-selective ligand, diarylpropionitrile (DPN). Results of these analyses demonstrated that the expression of ApoE is differentially regulated by ER␣ and ER␤. Activation of ER␣ increased, whereas activation of ER␤ decreased ApoE mRNA and protein expression in vitro and in vivo in rat hippocampus. Results Differential ApoE Expression in HT-22 Cells Transfected with ER␣ orER␤. To determine the ER subtype mediating E 2 regulation of ApoE, mouse hybrid HT-22 cel...

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“…Evidence suggests that, within the central nervous system, estrogen alters the expression of specific genes related to pain signaling to increase perception of peripheral nociceptive stimuli. [101][102][103] These estrogen-dependent alterations in gene expression increase neuronal excitability by promoting synaptic plasticity leading to increased visceral sensitivity in females, especially during periods of high cycling estrogen. 104 Another estrogenmediated mechanism that could drive visceral hypersensitivity is via the induction of µ-opioid receptor internalization within the medial preoptic nucleus and the posterodorsal medial amygdala.…”

Section: Sex Linked Differences In Visceral Sensitivitymentioning

confidence: 99%

Mechanisms of Stress-induced Visceral Pain

Meerveld

Johnson

2018

J Neurogastroenterol Motil

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Evidence suggests that long-term stress facilitates visceral pain through sensitization of pain pathways and promotes chronic visceral pain disorders such as the irritable bowel syndrome (IBS). This review will describe the importance of stress in exacerbating IBS-induced abdominal pain. Additionally, we will briefly review our understanding of the activation of the hypothalamic-pituitary-adrenal axis by both chronic adult stress and following early life stress in the pathogenesis of IBS. The review will focus on the glucocorticoid receptor and corticotropin-releasing hormone-mediated mechanisms in the amygdala involved in stress-induced visceral hypersensitivity. One potential mechanism underlying persistent effects of stress on visceral sensitivity could be epigenetic modulation of gene expression. While there are relatively few studies examining epigenetically mediated mechanisms involved in stress-induced visceral nociception, alterations in DNA methylation and histone acetylation patterns within the brain, have been linked to alterations in nociceptive signaling via increased expression of pro-nociceptive neurotransmitters. This review will discuss the latest studies investigating the long-term effects of stress on visceral sensitivity. Additionally, we will critically review the importance of experimental models of adult stress and early life stress in enhancing our understanding of the basic molecular mechanisms of nociceptive processing. Taken together, the complex clinical phenotype makes recapitulating IBS in rodent models extremely challenging. However, an aim of this review will be to describe how the use of rodent models of adult stress, early life stress (ELS), and a dysregulated HPA axis has improved our understanding of stress in the pathophysiology of IBS. Pathophysiology of Irritable Bowel Syndrome: Activation of the Brain-Gut AxisEvidence from clinical and basic research points to dysregulation of the bidirectional communication between the brain-gut axis in IBS. 21 The brain-gut axis represents a dynamic interplay between central circuits and peripheral mechanisms. The messengers of this complex circuit include neural, endocrine, metabolic, and immune mediators that are activated by central factors such as stress (Fig. 1). Although IBS is not an inflammatory disorder, the immune system plays a role in the pathogenesis of IBS in at least a subset of patients and likely contributes to the etiology of IBS symptoms. 22,23 A subset of IBS patients display a low grade chronic inflammation, and there is also evidence that following an enteric infection and combined with stressful life events, there is an increased risk of developed post-infectious IBS. [24][25][26][27] Clearly, the immune system and inflammatory processes are modulated by the HPA and autonomic nervous systems. In support, IBS patients also show increased number and reactivity of mast cells. 28,29 Data from peripheral blood mononuclear cells, as well as in mucosal biopsies, from IBS patients show that cytokines levels including TNF-α...

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Estrogen Receptor (ER)β Isoforms Rather Than ERα Regulate Corticotropin-Releasing Hormone Promoter Activity through an Alternate Pathway

Cited by 89 publications

References 55 publications

Sexually Dimorphic Responses of the Brain Norepinephrine System to Stress and Corticotropin-Releasing Factor

Sexually Dimorphic Responses of the Brain Norepinephrine System to Stress and Corticotropin-Releasing Factor

Activation of estrogen receptor α increases and estrogen receptor β decreases apolipoprotein E expression in hippocampus in vitro and in vivo

Mechanisms of Stress-induced Visceral Pain

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