The Experts below are selected from a list of 116253 Experts worldwide ranked by ideXlab platform
Paul G Mermelstein - One of the best experts on this subject based on the ideXlab platform.
-
the organizational and aromatization hypotheses apply to rapid nonclassical hormone action neonatal masculinization eliminates rapid Estradiol action in female hippocampal neurons
Endocrinology, 2012Co-Authors: John Meitzen, Danielle D Grove, Paul G MermelsteinAbstract:Early exposure to the steroid sex hormone testosterone and its estrogen metabolite Estradiol masculinize neural tissue during a developmental critical period. Many aspects of neuron anatomy and physiology are permanently altered, including later sensitivity to Estradiol. Although it is well established that early hormone exposure alters neuronal responsiveness regarding classical Estradiol actions (i.e. acting via nuclear estrogen receptors), it has not yet been determined whether it also alters neuronal processing of nonclassical estrogen receptor signaling, including the actions of membrane-associated estrogen receptors. Hence, we tested whether membrane estrogen receptor regulation of cAMP response element binding protein (CREB) phosphorylation observed in female (but not male) hippocampal pyramidal neurons is due to the lack of androgen and/or estrogen exposure in females during this critical period. Female rat neonates on postnatal d 0 and 1 were systemically injected with one of four compounds: vehicle, testosterone, the nonaromatizable androgen dihydrotestosterone, or Estradiol. On postnatal d 2, primary hippocampal neuron cultures were generated from these animals. After 8-9 d in culture, we assessed whether Estradiol affected CREB phosphorylation. Neurons from female neonates exposed to testosterone lacked Estradiol signaling to CREB. In contrast, dihydrotestosterone injections of female neonates did not disrupt Estradiol regulation of CREB. Estradiol injections of female neonates, however, eliminated Estradiol signaling to CREB. These findings indicate that testosterone aromatization to Estradiol leads to a masculinization/defeminization process whereby hippocampal neurons fail to exhibit rapid Estradiol signaling to CREB. Broadly, these findings extend the organizational and aromatization hypotheses to rapid, nonclassical hormone action.
-
Estradiol activates group i and ii metabotropic glutamate receptor signaling leading to opposing influences on camp response element binding protein
The Journal of Neuroscience, 2005Co-Authors: Marissa I Boulware, Jason P Weick, Bryan R Becklund, Rachel D Groth, Paul G MermelsteinAbstract:In addition to mediating sexual maturation and reproduction through stimulation of classical intracellular receptors that bind DNA and regulate gene expression, Estradiol is also thought to influence various brain functions by acting on receptors localized to the neuronal membrane surface. Many intracellular signaling pathways and modulatory proteins are affected by Estradiol via this unconventional route, including regulation of the transcription factor cAMP response element-binding protein (CREB). However, the mechanisms by which Estradiol acts at the membrane surface are poorly understood. Because both Estradiol and CREB have been implicated in regulating learning and memory, we characterized the effects of Estradiol on this transcription factor in cultured rat hippocampal neurons. Within minutes of administration, Estradiol triggered mitogen-activated protein kinase (MAPK)-dependent CREB phosphorylation in unstimulated neurons. Furthermore, after brief depolarization, Estradiol attenuated L-type calcium channel-mediated CREB phosphorylation. Thus, Estradiol exhibited both positive and negative influences on CREB activity. These effects of Estradiol were sex specific and traced to membrane-localized estrogen receptors that stimulated group I and II metabotropic glutamate receptor (mGluR) signaling. Activation of estrogen receptor α (ERα) led to mGluR1a signaling, triggering CREB phosphorylation through phospholipase C regulation of MAPK. In addition, Estradiol stimulation of ERα or ERβ triggered mGluR2/3 signaling, decreasing L-type calcium channel-mediated CREB phosphorylation. These results not only characterize Estradiol regulation of CREB but also provide two putative signaling mechanisms that may account for many of the unexplained observations regarding the influence of Estradiol on nervous system function.
-
Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor
The Journal of Neuroscience, 1996Co-Authors: Paul G Mermelstein, Jill B Becker, D. James SurmeierAbstract:Until recently, steroid hormones were believed to act only on cells containing intracellular receptors. However, recent evidence suggests that steroids have specific and rapid effects at the cellular membrane. Using whole-cell patch-clamp techniques, 17P-Estradiol was found to reduce Ba2+ entry reversibly via Ca”+ channels in acutely dissociated and cultured neostriatal neurons. The effects were sex-specific, i.e., the reduction of Ba”+ currents was greater in neurons taken from female rats. 17p-Estradiol primarily targeted L-type currents, and their inhibition was detected reliably within seconds of administration. The maximum reduction by 17P-Estradiol occurred at picomolar concentrations. 17P-Estradiol conjugated to bovine serum albumin also reduced Ba”+ currents, suggesting that the effect occurs at the membrane surface. Dialysis with GTPyS prevented reversal of the modulation, suggesting that 17P-Estradiol acts via G-protein activation. 17a-Estradiol also reduced Ba2+ currents but was significantly less effective than 17p-Estradiol. Estriol and 4-hydroxyEstradiol were found to reduce Ba2+ currents with similar efficacy to 17p-Estradiol, whereas estrone and 2-methoxyestriol were less effective. Tamoxifen also reduced Ba2+ currents but did not occlude the effect of 17P-Estradiol. These results suggest that at physiological concentrations, 17P-Estradiol can have immediate actions on neostriatal neurons via nongenomic signaling pathways.
-
Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor
The Journal of Neuroscience, 1996Co-Authors: Paul G Mermelstein, Jill B Becker, D. James SurmeierAbstract:Until recently, steroid hormones were believed to act only on cells containing intracellular receptors. However, recent evidence suggests that steroids have specific and rapid effects at the cellular membrane. Using whole-cell patch-clamp techniques, 17 beta-Estradiol was found to reduce Ba2+ entry reversibly via Ca2+ channels in acutely dissociated and cultured neostriatal neurons. The effects were sex-specific, i.e., the reduction of Ba2+ currents was greater in neurons taken from female rats. 17 beta-Estradiol primarily targeted L-type currents, and their inhibition was detected reliably within seconds of administration. The maximum reduction by 17 beta-Estradiol occurred at picomolar concentrations. 17 beta-Estradiol conjugated to bovine serum albumin also reduced Ba2+ currents, suggesting that the effect occurs at the membrane surface. Dialysis with GTP gamma S prevented reversal of the modulation, suggesting that 17 beta-Estradiol acts via G-protein activation. 17 alpha-Estradiol also reduced Ba2+ currents but was significantly less effective than 17 beta-Estradiol. Estriol and 4-hydroxyEstradiol were found to reduce Ba2+ currents with similar efficacy to 17 beta-Estradiol, whereas estrone and 2-methoxyestriol were less effective. Tamoxifen also reduced Ba2+ currents but did not occlude the effect of 17 beta-Estradiol. These results suggest that at physiological concentrations, 17 beta-Estradiol can have immediate actions on neostriatal neurons via nongenomic signaling pathways.
Jill B Becker - One of the best experts on this subject based on the ideXlab platform.
-
Estradiol induced potentiation of dopamine release in dorsal striatum following amphetamine administration requires Estradiol receptors and mglu5
eNeuro, 2019Co-Authors: Zhimin Song, Jill B Becker, Hongyan Yang, Elizabeth M PeckhamAbstract:Estradiol potentiates behavioral sensitization to cocaine as well as self-administration of cocaine and other drugs of abuse in female rodents. Furthermore, stimulated dopamine (DA) in the dorsolateral striatum (DLS) is rapidly enhanced by Estradiol, and it is hypothesized that this enhanced DA release mediates the more rapid escalation of drug taking seen in females, compared with males. The mechanisms mediating the effect of Estradiol to enhance stimulated DA release were investigated in this study. Using in vivo microdialysis and high performance liquid chromatography coupled with electrochemical detection, we first examined the effect of Estradiol on amphetamine-induced DA increase in the DLS of ovariectomized rats. We then tested whether the potentiation of this DA increase could be blocked by the Estradiol receptor antagonist, ICI 182,780 (ICI), or an antagonist to the metabotropic glutamate receptor subtype 5 (mGlu5), 2-methyl-6-(phenylethynyl)pyridine (MPEP). There is evidence that Estradiol receptors collaborate with mGlu5 within caveoli in DLS and mGlu5 is hypothesized to mediate many of the effects of Estradiol in the addiction processes in females. Our data show that Estradiol enhances the DA response to amphetamine. Either ICI or MPEP prevented the effect of Estradiol to enhance DA release. Importantly, our results also showed that neither ICI or MPEP alone is able to influence the DA response to amphetamine when Estradiol is not administrated, suggesting that ICI and MPEP act via Estradiol receptors. Together, our findings demonstrate that Estradiol potentiates amphetamine-stimulated DA release in the DLS and this effect requires both Estradiol receptors and mGlu5.
-
Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor
The Journal of Neuroscience, 1996Co-Authors: Paul G Mermelstein, Jill B Becker, D. James SurmeierAbstract:Until recently, steroid hormones were believed to act only on cells containing intracellular receptors. However, recent evidence suggests that steroids have specific and rapid effects at the cellular membrane. Using whole-cell patch-clamp techniques, 17P-Estradiol was found to reduce Ba2+ entry reversibly via Ca”+ channels in acutely dissociated and cultured neostriatal neurons. The effects were sex-specific, i.e., the reduction of Ba”+ currents was greater in neurons taken from female rats. 17p-Estradiol primarily targeted L-type currents, and their inhibition was detected reliably within seconds of administration. The maximum reduction by 17P-Estradiol occurred at picomolar concentrations. 17P-Estradiol conjugated to bovine serum albumin also reduced Ba”+ currents, suggesting that the effect occurs at the membrane surface. Dialysis with GTPyS prevented reversal of the modulation, suggesting that 17P-Estradiol acts via G-protein activation. 17a-Estradiol also reduced Ba2+ currents but was significantly less effective than 17p-Estradiol. Estriol and 4-hydroxyEstradiol were found to reduce Ba2+ currents with similar efficacy to 17p-Estradiol, whereas estrone and 2-methoxyestriol were less effective. Tamoxifen also reduced Ba2+ currents but did not occlude the effect of 17P-Estradiol. These results suggest that at physiological concentrations, 17P-Estradiol can have immediate actions on neostriatal neurons via nongenomic signaling pathways.
-
Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor
The Journal of Neuroscience, 1996Co-Authors: Paul G Mermelstein, Jill B Becker, D. James SurmeierAbstract:Until recently, steroid hormones were believed to act only on cells containing intracellular receptors. However, recent evidence suggests that steroids have specific and rapid effects at the cellular membrane. Using whole-cell patch-clamp techniques, 17 beta-Estradiol was found to reduce Ba2+ entry reversibly via Ca2+ channels in acutely dissociated and cultured neostriatal neurons. The effects were sex-specific, i.e., the reduction of Ba2+ currents was greater in neurons taken from female rats. 17 beta-Estradiol primarily targeted L-type currents, and their inhibition was detected reliably within seconds of administration. The maximum reduction by 17 beta-Estradiol occurred at picomolar concentrations. 17 beta-Estradiol conjugated to bovine serum albumin also reduced Ba2+ currents, suggesting that the effect occurs at the membrane surface. Dialysis with GTP gamma S prevented reversal of the modulation, suggesting that 17 beta-Estradiol acts via G-protein activation. 17 alpha-Estradiol also reduced Ba2+ currents but was significantly less effective than 17 beta-Estradiol. Estriol and 4-hydroxyEstradiol were found to reduce Ba2+ currents with similar efficacy to 17 beta-Estradiol, whereas estrone and 2-methoxyestriol were less effective. Tamoxifen also reduced Ba2+ currents but did not occlude the effect of 17 beta-Estradiol. These results suggest that at physiological concentrations, 17 beta-Estradiol can have immediate actions on neostriatal neurons via nongenomic signaling pathways.
Raghvendra K Dubey - One of the best experts on this subject based on the ideXlab platform.
-
Estradiol metabolites inhibit endothelin synthesis by an estrogen receptor independent mechanism
Hypertension, 2001Co-Authors: Raghvendra K Dubey, Edwin K Jackson, Paul J Keller, Bruno Imthurn, Marinella RosselliAbstract:Estradiol inhibits endothelin-1 synthesis, an effect that may contribute to the cardiovascular protective effects of Estradiol. Recent findings that Estradiol inhibits neointima formation in mice lacking estrogen receptors suggests that the cardiovascular protective effects of Estradiol may be mediated by means of an estrogen receptor-independent mechanism. Because 2-hydroxyEstradiol and 2-methoxyEstradiol, metabolites of Estradiol with little/no affinity for estrogen receptors, are more potent than Estradiol in inhibiting vascular smooth muscle cell growth, we investigated whether these metabolites also inhibit endothelin-1 synthesis by means of an receptor-independent mechanism. Treatment of porcine coronary artery endothelial cells for 4 to 24 hours with 0.001 to 1 μmol/L of Estradiol, 2-hydroxyEstradiol, or 2-methoxyEstradiol concentration-dependently inhibited basal as well as serum-induced (2.5%), TNFα-induced (10 ng/mL), angiotensin II–induced (100 nmol/L), and thrombin-induced (4 U/mL) endothelin-1 synthesis. Estradiol, 2-hydroxyEstradiol, and 2-methoxyEstradiol also inhibited serum-induced mitogen-activated protein kinase activity. As compared with Estradiol, its metabolites were more potent in inhibiting endothelin-1 secretion and mitogen activated protein kinase activity. The inhibitory effects of 2-hydroxyEstradiol and 2-methoxyEstradiol on endothelin-1 release and mitogen-activated protein kinase activity were not blocked by ICI182780 (50 μmol/L), an estrogen receptor antagonist. Our findings indicate that the Estradiol metabolites 2-hydroxyEstradiol and 2-methoxyEstradiol potently inhibit endothelin-1 synthesis by means of an estrogen receptor-independent mechanism. This effect of Estradiol metabolites may be mediated by inhibition of mitogen activated protein kinase activity and may contribute to the cardioprotective effects of Estradiol.
-
methoxyEstradiols mediate the antimitogenic effects of Estradiol on vascular smooth muscle cells via estrogen receptor independent mechanisms
Biochemical and Biophysical Research Communications, 2000Co-Authors: Raghvendra K Dubey, Marinella Rosselli, Delbert G Gillespie, Lefteris C Zacharia, Kenneth R Korzekwa, Juergen Fingerle, Edwin K JacksonAbstract:Abstract Estrogen receptors (ERs) are widely held to mediate the ability of 17β-Estradiol (Estradiol) to attenuate injury-induced proliferation of vascular smooth muscle cells (VSMCs) leading to vascular lesions. However, recent findings that Estradiol prevents injury-induced vascular lesion formation in knock-out mice lacking either ERα or ERβ seriously challenge this concept. Here we report that the local metabolism of Estradiol to methoxyEstradiols, endogenous metabolites of Estradiol with no affinity for ERs, is responsible for the ER-independent inhibitory effects of locally applied Estradiol on rat VSMC growth. These finding imply that local vascular Estradiol metabolism may be an important determinant of the cardiovascular protective effects of circulating Estradiol. Thus, interindividual differences, either genetic or acquired, in the vascular metabolism of Estradiol may define a given female's risk of cardiovascular disease and influence the cardiovascular benefit she receives from Estradiol replacement therapy in the postmenopausal state. These findings also imply that nonfeminizing Estradiol metabolites may confer cardiovascular protection in both women and men.
D. James Surmeier - One of the best experts on this subject based on the ideXlab platform.
-
Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor
The Journal of Neuroscience, 1996Co-Authors: Paul G Mermelstein, Jill B Becker, D. James SurmeierAbstract:Until recently, steroid hormones were believed to act only on cells containing intracellular receptors. However, recent evidence suggests that steroids have specific and rapid effects at the cellular membrane. Using whole-cell patch-clamp techniques, 17P-Estradiol was found to reduce Ba2+ entry reversibly via Ca”+ channels in acutely dissociated and cultured neostriatal neurons. The effects were sex-specific, i.e., the reduction of Ba”+ currents was greater in neurons taken from female rats. 17p-Estradiol primarily targeted L-type currents, and their inhibition was detected reliably within seconds of administration. The maximum reduction by 17P-Estradiol occurred at picomolar concentrations. 17P-Estradiol conjugated to bovine serum albumin also reduced Ba”+ currents, suggesting that the effect occurs at the membrane surface. Dialysis with GTPyS prevented reversal of the modulation, suggesting that 17P-Estradiol acts via G-protein activation. 17a-Estradiol also reduced Ba2+ currents but was significantly less effective than 17p-Estradiol. Estriol and 4-hydroxyEstradiol were found to reduce Ba2+ currents with similar efficacy to 17p-Estradiol, whereas estrone and 2-methoxyestriol were less effective. Tamoxifen also reduced Ba2+ currents but did not occlude the effect of 17P-Estradiol. These results suggest that at physiological concentrations, 17P-Estradiol can have immediate actions on neostriatal neurons via nongenomic signaling pathways.
-
Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor
The Journal of Neuroscience, 1996Co-Authors: Paul G Mermelstein, Jill B Becker, D. James SurmeierAbstract:Until recently, steroid hormones were believed to act only on cells containing intracellular receptors. However, recent evidence suggests that steroids have specific and rapid effects at the cellular membrane. Using whole-cell patch-clamp techniques, 17 beta-Estradiol was found to reduce Ba2+ entry reversibly via Ca2+ channels in acutely dissociated and cultured neostriatal neurons. The effects were sex-specific, i.e., the reduction of Ba2+ currents was greater in neurons taken from female rats. 17 beta-Estradiol primarily targeted L-type currents, and their inhibition was detected reliably within seconds of administration. The maximum reduction by 17 beta-Estradiol occurred at picomolar concentrations. 17 beta-Estradiol conjugated to bovine serum albumin also reduced Ba2+ currents, suggesting that the effect occurs at the membrane surface. Dialysis with GTP gamma S prevented reversal of the modulation, suggesting that 17 beta-Estradiol acts via G-protein activation. 17 alpha-Estradiol also reduced Ba2+ currents but was significantly less effective than 17 beta-Estradiol. Estriol and 4-hydroxyEstradiol were found to reduce Ba2+ currents with similar efficacy to 17 beta-Estradiol, whereas estrone and 2-methoxyestriol were less effective. Tamoxifen also reduced Ba2+ currents but did not occlude the effect of 17 beta-Estradiol. These results suggest that at physiological concentrations, 17 beta-Estradiol can have immediate actions on neostriatal neurons via nongenomic signaling pathways.
Ferdinando Auricchio - One of the best experts on this subject based on the ideXlab platform.
-
hormone dependent nuclear export of Estradiol receptor and dna synthesis in breast cancer cells
Journal of Cell Biology, 2008Co-Authors: Maria Lombardi, Antimo Migliaccio, Gabriella Castoria, Maria Vittoria Barone, Rosina Di Stasio, Alessandra Ciociola, Daniela Bottero, Ettore Appella, Hiroshi Yamaguchi, Ferdinando AuricchioAbstract:In breast cancer cells, cytoplasmic localization of the Estradiol receptor α (ERα) regulates Estradiol-dependent S phase entry. We identified a nuclear export sequence (NES) in ERα and show that its export is dependent on both Estradiol-mediated phosphatidylinositol-3-kinase (PI3K)/AKT activation and chromosome region maintenance 1 (CRM1). A Tat peptide containing the ERα NES disrupts ERα–CRM1 interaction and prevents nuclear export of ERα- and Estradiol-induced DNA synthesis. NES-ERα mutants do not exit the nucleus and inhibit Estradiol-induced S phase entry; ERα-dependent transcription is normal. ERα is associated with Forkhead proteins in the nucleus, and Estradiol stimulates nuclear exit of both proteins. ERα knockdown or ERα NES mutations prevent ERα and Forkhead nuclear export. A mutant of forkhead in rhabdomyosarcoma (FKHR), which cannot be phosphorylated by Estradiol-activated AKT, does not associate with ERα and is trapped in the nucleus, blocking S phase entry. In conclusion, Estradiol-induced AKT-dependent phosphorylation of FKHR drives its association with ERα, thereby triggering complex export from the nucleus necessary for initiation of DNA synthesis and S phase entry.
-
tyrosine kinase p21ras map kinase pathway activation by Estradiol receptor complex in mcf 7 cells
The EMBO Journal, 1996Co-Authors: Antimo Migliaccio, Gabriella Castoria, E. Nola, M. Di Domenico, Paola Bontempo, Antonietta De Falco, Ferdinando AuricchioAbstract:The mechanism by which Estradiol acts on cell multiplication is still unclear. Under conditions of Estradiol-dependent growth, Estradiol treatment of human mammary cancer MCF-7 cells triggers rapid and transient activation of the mitogen-activated (MAP) kinases, erk-1 and erk-2, increases the active form of p21ras, tyrosine phosphorylation of Shc and p190 protein and induces association of p190 to p21ras-GAP. Both Shc and p190 are substrates of activated src and once phosphorylated, they interact with other proteins and upregulate p21ras. Estradiol activates the tyrosine kinase/p21ras/MAP-kinase pathway in MCF-7 cells with kinetics which are similar to those of peptide mitogens. It is only after introduction of the human wild-type 67 kDa Estradiol receptor cDNA that Cos cells become Estradiol-responsive in terms of erk-2 activity. This finding, together with the inhibition by the pure anti-estrogen ICI 182 780 of the stimulatory effect of Estradiol on each step of the pathway in MCF-7 cells proves that the classic Estradiol receptor is responsible for the transduction pathway activation. Transfection experiments of Cos cells with the Estradiol receptor cDNA and in vitro experiments with c-src show that the Estradiol receptor activates c-src and this activation requires occupancy of the receptor by hormone. Our experiments suggest that c-src is an initial and integral part of the signaling events mediated by the Estradiol receptor.
