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Cheryl S Watson - One of the best experts on this subject based on the ideXlab platform.
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combinations of physiologic Estrogens with xenoEstrogens alter calcium and kinase responses prolactin release and Membrane Estrogen Receptor trafficking in rat pituitary cells
Environmental Health, 2010Co-Authors: Yow Jiun Jeng, Mikhail Y Kochukov, Cheryl S WatsonAbstract:Background XenoEstrogens such as alkylphenols and the structurally related plastic byproduct bisphenol A have recently been shown to act potently via nongenomic signaling pathways and the Membrane version of Estrogen Receptor-α. Though the responses to these compounds are typically measured individually, they usually contaminate organisms that already have endogenous Estrogens present. Therefore, we used quantitative medium-throughput screening assays to measure the effects of physiologic Estrogens in combination with these xenoEstrogens.
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Proliferative and anti-proliferative effects of dietary levels of phytoEstrogens in rat pituitary GH3/B6/F10 cells - the involvement of rapidly activated kinases and caspases
BMC Cancer, 2009Co-Authors: Yow Jiun Jeng, Cheryl S WatsonAbstract:Phytoestogens are a group of lipophillic plant compounds that can have Estrogenic effects in animals; both tumorigenic and anti-tumorigenic effects have been reported. Prolactin-secreting adenomas are the most prevalent form of pituitary tumors in humans and have been linked to Estrogen exposures. We examined the proliferative effects of phytoEstrogens on a rat pituitary tumor cell line, GH3/B6/F10, originally subcloned from GH3 cells based on its ability to express high levels of the Membrane Estrogen Receptor-α.
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Membrane Estrogen Receptor-α-mediated nongenomic actions of phytoEstrogens in GH_3/B_6/F_10 pituitary tumor cells
Journal of Molecular Signaling, 2009Co-Authors: Yow Jiun Jeng, Mikhail Y Kochukov, Cheryl S WatsonAbstract:Background Estradiol (E_2) mediates various intracellular signaling cascades from the plasma Membrane via several Estrogen Receptors (ERs). The pituitary is an Estrogen-responsive tissue, and we have previously reported that E_2 can activate mitogen-activated protein kinases (MAPKs) such as ERK1/2 and JNK1/2/3 in the Membrane ERα (mERα)-enriched GH_3/B_6/F_10 rat pituitary tumor cell line. PhytoEstrogens are compounds found in plants and foods such as soybeans, alfalfa sprouts, and red grapes. They are structurally similar to E_2 and share a similar mechanism of action through their binding to ERs. PhytoEstrogens bind to nuclear ERs with a much lower affinity and therefore are less potent in mediating genomic responses. However, little is known about their ability to act via mERs to mediate nongenomic effects. Methods To investigate the activation of different nongenomic pathways, and determine the involvement of mERα, we measured prolactin (PRL) release by radio-immunoassay, MAPK activations (ERK1/2 and JNK1/2/3) via a quantitative plate immunoassay, and intracellular [Ca^2+] by Fura-2 fluorescence imaging in cells treated with E_2 or four different phytoEstrogens (coumestrol, daidzein, genistein, and trans -resveratrol). Results Coumesterol and daidzein increased PRL release similar to E_2 in GH_3/B_6/F_10 cells, while genistein and trans -resveratrol had no effect. All of these compounds except genistein activated ERK1/2 signaling at 1–10 picomolar concentrations; JNK 1/2/3 was activated by all compounds at a 100 nanomolar concentration. All compounds also caused rapid Ca^2+ uptake, though in unique dose-dependent Ca^2+ response patterns for several aspects of this response. A subclone of GH_3 cells expressing low levels of mERα (GH_3/B_6/D_9) did not respond to any phytoEstrogen treatments for any of these responses, suggesting that these nongenomic effects were mediated via mERα. Conclusion PhytoEstrogens were much more potent in mediating these nongenomic responses (activation of MAPKs, PRL release, and increased intracellular [Ca^2+]) via mERα than was previously reported for genomic responses. The unique non-monotonic dose responses and variant signaling patterns caused by E_2 and all tested phytoEstrogens suggest that complex and multiple signaling pathways or binding partners could be involved. By activating these different nongenomic signaling pathways, phytoEstrogens could have significant physiological consequences for pituitary cell functions.
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Membrane Estrogen Receptor α mediated nongenomic actions of phytoEstrogens in gh3 b6 f10 pituitary tumor cells
Journal of Molecular Signaling, 2009Co-Authors: Yow Jiun Jeng, Mikhail Y Kochukov, Cheryl S WatsonAbstract:Background Estradiol (E2) mediates various intracellular signaling cascades from the plasma Membrane via several Estrogen Receptors (ERs). The pituitary is an Estrogen-responsive tissue, and we have previously reported that E2 can activate mitogen-activated protein kinases (MAPKs) such as ERK1/2 and JNK1/2/3 in the Membrane ERα (mERα)-enriched GH3/B6/F10 rat pituitary tumor cell line. PhytoEstrogens are compounds found in plants and foods such as soybeans, alfalfa sprouts, and red grapes. They are structurally similar to E2 and share a similar mechanism of action through their binding to ERs. PhytoEstrogens bind to nuclear ERs with a much lower affinity and therefore are less potent in mediating genomic responses. However, little is known about their ability to act via mERs to mediate nongenomic effects.
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the roles of Membrane Estrogen Receptor subtypes in modulating dopamine transporters in pc 12 cells
Journal of Neurochemistry, 2008Co-Authors: Rebecca A Alyea, Stephanie E Laurence, John A Katzenellenbogen, Benita S. Katzenellenbogen, Cheryl S WatsonAbstract:The effects of 17β-estradiol (E2) on dopamine (DA) transport could explain gender and life-stage differences in the incidence of some neurological disorders. We tested the effects of E2 at physiological concentrations on DA efflux in nerve growth factor-differentiated rat pheochromocytoma cells that express Estrogen Receptors (ER) α, ERβ, and G-protein coupled Receptor 30 (GPR30), and DA transporter (DAT). DAT efflux was determined as the transporter-specific loss of 3H-DA from pre-loaded cells; a 9–15 min 10−9 M E2 treatment caused maximal DA efflux. Such rapid Estrogenic action suggests a non-genomic response, and an E2-dendrimer conjugate (limited to non-nuclear actions) caused DA efflux within 5 min. Efflux dose–responses for E2 were non-monotonic, also characteristic of non-genomic Estrogenic actions. ERα siRNA knockdown abolished E2-mediated DA efflux, while ERβ knockdown did not, and GPR30 knockdown increased E2-mediated DA efflux (suggesting GPR30 is inhibitory). Use of ER-selective agonists/antagonists demonstrated that ERα is the predominant mediator of E2-mediated DA efflux, with inhibitory contributions from GPR30 and ERβ. E2 also caused trafficking of ERα to the plasma Membrane, trafficking of ERβ away from the plasma Membrane, and unchanged Membrane GPR30 levels. Therefore, ERα is largely responsible for non-genomic Estrogenic effects on DAT activity.
Paul E Micevych - One of the best experts on this subject based on the ideXlab platform.
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A Novel Membrane Estrogen Receptor Activated by STX Induces Female Sexual Receptivity through an Interaction with mGluR1a.
Neuroendocrinology, 2013Co-Authors: Amy Christensen, Paul E MicevychAbstract:Membrane initiated estradiol signaling has been shown to be vital for multiple physiological processes. Several Receptors have been proposed to mediate the actions of estradiol at the Membrane. Here, we examined the ability of STX, an agonist of a novel putative Membrane Estrogen Receptor, to activate sexually receptive behavior in the female rat. Infusions of STX into the arcuate nucleus of the hypothalamus resulted in the activation and internalization of μ-opioid Receptors in the medial preoptic nucleus, an action that is required for lordosis behavior. Indeed, STX was able to augment sexual receptivity in female rats given a sub-behavioral dose of estradiol. However, if the mGluR1a antagonist, LY367,385, was administered prior to STX, its circuit-activating effects, the internalization of μ-opioid Receptors, were lost. This suggests that the Receptor stimulated by STX activates rapid Membrane-initiated signaling through an interaction with mGluR1a – an effect previously described for Estrogen Receptor-α at the Membrane.
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cav1 sirna reduces Membrane Estrogen Receptor α levels and attenuates sexual receptivity
Endocrinology, 2012Co-Authors: Amy Christensen, Paul E MicevychAbstract:Although classic Estrogen Receptors (ER) have been proposed to mediate estradiol signaling, it has been relatively recently that mechanisms of trafficking these Receptors have been elucidated. ERα is palmitoylated and associates with caveolin proteins to be targeted to the cell Membrane. Caveolins are scaffold proteins that not only traffic ERα to the Membrane but also are involved in establishing metabotropic glutamate Receptor interactions that are necessary for activating G protein signaling. To demonstrate the role of caveolin proteins in regulating an estradiol-dependent behavior, sexual receptivity, we used small interfering RNA to knock down caveolin-1 (CAV1) expression in the arcuate nucleus of the hypothalamus. In CAV1 knockdown rats, Membrane, but not intracellular levels of ERα, were significantly reduced. As expected, Estrogenic stimulation of the arcuate nucleus of the hypothalamus to medial preoptic nucleus projection was abrogated in CAV1 knockdown rats, indicating that the Membrane-initiated activation of this circuit was compromised. Moreover, estradiol-induced lordosis behavior that is dependent on activation of μ-opioid Receptors in the medial preoptic nucleus was also significantly reduced. Thus, CAV1-mediated ERα trafficking to the cell Membrane is required for estradiol activation of circuits underlying female sexual receptivity.
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Membrane Estrogen Receptor regulation of hypothalamic function
Neuroendocrinology, 2012Co-Authors: Paul E Micevych, Martin J KellyAbstract:Over the decades, our understanding of Estrogen Receptor (ER) function has evolved. Today we are confronted by at least two nuclear ERs, ERα and ERβ, and a number of putative Membrane ERs, including ERα, ERβ, ER-X, GPR30 and Gq-mER. These Receptors all bind Estrogens or at least Estrogenic compounds and activate intracellular signaling pathways. In some cases, a well-defined pharmacology and physiology has been discovered. In other cases, the identity or the function remains to be elucidated. This mini-review attempts to synthesize our understanding of 17β-estradiol Membrane signaling within hypothalamic circuits involved in homeostatic functions, focusing on reproduction and energy balance.
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Estradiol attenuates the adenosine triphosphate-induced increase of intracellular calcium through group II metabotropic glutamate Receptors in rat dorsal root ganglion neurons.
Journal of neuroscience research, 2011Co-Authors: Vitaly V. Chaban, John S. Mcdonald, Andrea J. Rapkin, Paul E MicevychAbstract:Estradiol attenuates the ATP-induced increase of intracellular calcium concentration ([Ca(2+)](i)) in rat dorsal root ganglion (DRG) neurons by blocking the L-type voltage gated calcium channel (VGCC). Because ATP is a putative nociceptive signal, this action may indicate a site of estradiol regulation of pain. In other neurons, 17β-estradiol (E(2)) has been shown to modulate L-type VGCC through a Membrane Estrogen Receptor-group II metabotropic glutamate Receptor (mGluR(2/3)). The present study investigated whether the rapid estradiol attenuation of the ATP-induced increase in [Ca(2+)](i) requires mGluR(2/3). Previously we showed that DRG (L(1)-S(3)) express ERα, P2X(3), and mGluR(2/3) Receptors. DRG were acutely dissociated by enzyme digestion and grown in short-term culture for imaging analysis. DRG neurons were stimulated twice, once with ATP (50 μM) for 5 sec and then again in the presence of E(2) (100 nM) or E(2) (100 nM) + LY341495 (100 nM), an mGluR(2/3) inhibitor. ATP induced a transient increase in [Ca(2+)](i) (216.3 ± 41.2 nM). This transient increase could be evoked several times in the same DRG neurons if separated by a 5-min washout. Treatment with estradiol significantly attenuated the ATP-induced [Ca(2+)](i) increase in 60% of the DRG neurons, to 163.3 ± 20.9 nM (P 0.05). These data indicate that the rapid action of E(2) in DRG neurons is dependent on mGluR(2/3) and demonstrate that Membrane Estrogen Receptor-α-initiated signaling involves interaction with mGluRs.
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estradiol rapidly regulates Membrane Estrogen Receptor α levels in hypothalamic neurons
The Journal of Neuroscience, 2010Co-Authors: Reymundo Dominguez, Paul E MicevychAbstract:Estrogen Receptors (ERs) and Estrogen-binding proteins have been localized intracellularly and on the cell surface. The Membrane-associated proteins initiate signaling that activates a myriad of cellular responses including the modulation of ion channels and ultimately transcription. Although many of the downstream actions of Membrane ERs, including ERα and ERβ, have been characterized, the mechanisms regulating Membrane ER levels have remained elusive in the nervous system. In the present study, we used surface biotinylation to identify and study the estradiol regulation of Membrane ERα in mixed-sex, cultured hypothalamic neurons from rat. Following surface biotinylation, Western blot analysis revealed full-length 66 kDa ERα and several ERα splice variants, most notably a biotinylated 52 kDa ERα-immunoreactive protein. Treatment of the neurons with estradiol caused a rapid and transient increase of the biotinylated 52 kDa and 66 kDa ERα proteins in the plasma Membrane. Exposure of the neurons to estradiol also significantly increased internalization of 52 kDa and 66 kDa ERα Membrane proteins, a measure of Receptor activation. In the hypothalamus, Membrane ERα signaling depends on transactivation of metabotropic glutamate Receptor-1a (mGluR1a). Estradiol treatment increased the internalization of mGluR1a in parallel with ERα, a finding consistent with the hypothesis of an ERα-mGluR1a signaling unit. These results demonstrate that estradiol regulates the amount of ERα in the Membrane, suggesting estradiol can regulate its own Membrane signaling.
Martin J Kelly - One of the best experts on this subject based on the ideXlab platform.
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the Membrane Estrogen Receptor ligand stx rapidly enhances gabaergic signaling in npy agrp neurons role in mediating the anorexigenic effects of 17β estradiol
American Journal of Physiology-endocrinology and Metabolism, 2013Co-Authors: Arik W Smith, Martin J Kelly, Oline K. Rønnekleiv, Martha A Bosch, Edward J WagnerAbstract:Besides its quintessential role in reproduction, 17β-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled Membrane Estrogen Receptor (Gq-mER) ligand STX rapidly increase...
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the Membrane Estrogen Receptor ligand stx rapidly enhances gabaergic signaling in npy agrp neurons role in mediating the anorexigenic effects of 17β estradiol
American Journal of Physiology-endocrinology and Metabolism, 2013Co-Authors: Arik W Smith, Martin J Kelly, Oline K. Rønnekleiv, Martha A Bosch, Edward J WagnerAbstract:Besides its quintessential role in reproduction, 17β-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled Membrane Estrogen Receptor (Gq-mER) ligand STX rapidly increase Membrane excitability in proopiomelanocortin (POMC) neurons by desensitizing the coupling of GABAB Receptors to G protein-coupled inwardly rectifying K+ channels (GIRKs), which upon activation elicit a hyperpolarizing outward current. However, it is unknown whether E2 and STX can modulate GABAB signaling in neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. We used single-cell RT-PCR and whole cell patch clamping with selective pharmacological reagents to show that NPY/AgRP cells of mice express the GABAB-R1 and -R2 Receptors and are hyperpolarized by the GABAB agonist baclofen in an E2-dependent manner. In males, E2 rapidly attenuated the coupling of GABAB Receptors to GIRKs, which was blocked by the general PI3K inhibitors wortmannin and LY-294002 or the selective p110β subunit inhibitor TGX-221. The ERα-selective agonist propyl pyrazole triol mimicked the effects of E2. STX, in contrast, enhanced the GABAB response in males, which was abrogated by the Estrogen Receptor (ER) antagonist ICI 182,780. In gonadectomized mice of both sexes, E2 enhanced or attenuated the GABAB response in different NPY/AgRP cells. Coperfusing wortmannin with E2 or simply applying STX always enhanced the GABAB response. Thus, in NPY/AgRP neurons, activation of the Gq-mER by E2 or STX enhances the GABAergic postsynaptic response, whereas activation of ERα by E2 attenuates it. These findings demonstrate a clear functional dichotomy of rapid E2 Membrane-initiated signaling via ERα vs. Gq-mER in a CNS neuron vital for regulating energy homeostasis.
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The Membrane Estrogen Receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17β-estradiol.
American Journal of Physiology-endocrinology and Metabolism, 2013Co-Authors: Arik W Smith, Oline K. Rønnekleiv, Martha A Bosch, Edward J Wagner, Martin J KellyAbstract:Besides its quintessential role in reproduction, 17β-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled Membrane Estrogen Receptor (Gq-mER) ligand STX rapidly increase Membrane excitability in proopiomelanocortin (POMC) neurons by desensitizing the coupling of GABAB Receptors to G protein-coupled inwardly rectifying K+ channels (GIRKs), which upon activation elicit a hyperpolarizing outward current. However, it is unknown whether E2 and STX can modulate GABAB signaling in neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. We used single-cell RT-PCR and whole cell patch clamping with selective pharmacological reagents to show that NPY/AgRP cells of mice express the GABAB-R1 and -R2 Receptors and are hyperpolarized by the GABAB agonist baclofen in an E2-dependent manner. In males, E2 rapidly attenuated the coupling of GABAB Receptors to GIRKs, which was blocked by the general PI3K inhibitors wortmannin and LY-294002 or the selective p110β subunit inhibitor TGX-221. The ERα-selective agonist propyl pyrazole triol mimicked the effects of E2. STX, in contrast, enhanced the GABAB response in males, which was abrogated by the Estrogen Receptor (ER) antagonist ICI 182,780. In gonadectomized mice of both sexes, E2 enhanced or attenuated the GABAB response in different NPY/AgRP cells. Coperfusing wortmannin with E2 or simply applying STX always enhanced the GABAB response. Thus, in NPY/AgRP neurons, activation of the Gq-mER by E2 or STX enhances the GABAergic postsynaptic response, whereas activation of ERα by E2 attenuates it. These findings demonstrate a clear functional dichotomy of rapid E2 Membrane-initiated signaling via ERα vs. Gq-mER in a CNS neuron vital for regulating energy homeostasis.
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The Membrane Estrogen Receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17β-estradiol.
American journal of physiology. Endocrinology and metabolism, 2013Co-Authors: Arik W Smith, Oline K. Rønnekleiv, Martha A Bosch, Edward J Wagner, Martin J KellyAbstract:Besides its quintessential role in reproduction, 17β-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled Membrane Estrogen Receptor (Gq-mER) ligand STX rapidly increase...
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rapid effects of 17β estradiol on male copulatory behaviors are not elicited by the novel Membrane active Estrogenic compound stx
Behavioral Neuroscience, 2013Co-Authors: Katherine R Kaufman, Martin J Kelly, Charles E RoselliAbstract:Estrogens have been shown to rapidly promote male copulatory behaviors with a time-course that suggests rapid signaling events are involved. The present study tested the hypothesis that Estrogen acts through a novel Gq protein-coupled Membrane Estrogen Receptor (ER). Thus, either estradiol (E2), STX (a diphenylacrylamide compound that selectively activates a Membrane ER pathway), or vehicle were administered acutely to castrated male rats that bore sc dihydrotestosterone implants to maintain genital sensitivity. Appetitive (level changes, genital investigation) and consummatory (mounts, intromissions, ejaculations) components of male sexual behavior were measured in a bilevel testing apparatus. Testing showed that E2 treatment promoted olfactory and mounting behaviors, but had no effect on motivation as measured by anticipatory level changes. STX treatment showed no effect on either component of male sexual behavior. These results support previous results that showed that E2 can rapidly affect male sexual behaviors, but fail to support a role for the specific Membrane-initiated pathway activated by STX.
Oline K. Rønnekleiv - One of the best experts on this subject based on the ideXlab platform.
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the Membrane Estrogen Receptor ligand stx rapidly enhances gabaergic signaling in npy agrp neurons role in mediating the anorexigenic effects of 17β estradiol
American Journal of Physiology-endocrinology and Metabolism, 2013Co-Authors: Arik W Smith, Martin J Kelly, Oline K. Rønnekleiv, Martha A Bosch, Edward J WagnerAbstract:Besides its quintessential role in reproduction, 17β-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled Membrane Estrogen Receptor (Gq-mER) ligand STX rapidly increase Membrane excitability in proopiomelanocortin (POMC) neurons by desensitizing the coupling of GABAB Receptors to G protein-coupled inwardly rectifying K+ channels (GIRKs), which upon activation elicit a hyperpolarizing outward current. However, it is unknown whether E2 and STX can modulate GABAB signaling in neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. We used single-cell RT-PCR and whole cell patch clamping with selective pharmacological reagents to show that NPY/AgRP cells of mice express the GABAB-R1 and -R2 Receptors and are hyperpolarized by the GABAB agonist baclofen in an E2-dependent manner. In males, E2 rapidly attenuated the coupling of GABAB Receptors to GIRKs, which was blocked by the general PI3K inhibitors wortmannin and LY-294002 or the selective p110β subunit inhibitor TGX-221. The ERα-selective agonist propyl pyrazole triol mimicked the effects of E2. STX, in contrast, enhanced the GABAB response in males, which was abrogated by the Estrogen Receptor (ER) antagonist ICI 182,780. In gonadectomized mice of both sexes, E2 enhanced or attenuated the GABAB response in different NPY/AgRP cells. Coperfusing wortmannin with E2 or simply applying STX always enhanced the GABAB response. Thus, in NPY/AgRP neurons, activation of the Gq-mER by E2 or STX enhances the GABAergic postsynaptic response, whereas activation of ERα by E2 attenuates it. These findings demonstrate a clear functional dichotomy of rapid E2 Membrane-initiated signaling via ERα vs. Gq-mER in a CNS neuron vital for regulating energy homeostasis.
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the Membrane Estrogen Receptor ligand stx rapidly enhances gabaergic signaling in npy agrp neurons role in mediating the anorexigenic effects of 17β estradiol
American Journal of Physiology-endocrinology and Metabolism, 2013Co-Authors: Arik W Smith, Martin J Kelly, Oline K. Rønnekleiv, Martha A Bosch, Edward J WagnerAbstract:Besides its quintessential role in reproduction, 17β-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled Membrane Estrogen Receptor (Gq-mER) ligand STX rapidly increase...
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The Membrane Estrogen Receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17β-estradiol.
American Journal of Physiology-endocrinology and Metabolism, 2013Co-Authors: Arik W Smith, Oline K. Rønnekleiv, Martha A Bosch, Edward J Wagner, Martin J KellyAbstract:Besides its quintessential role in reproduction, 17β-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled Membrane Estrogen Receptor (Gq-mER) ligand STX rapidly increase Membrane excitability in proopiomelanocortin (POMC) neurons by desensitizing the coupling of GABAB Receptors to G protein-coupled inwardly rectifying K+ channels (GIRKs), which upon activation elicit a hyperpolarizing outward current. However, it is unknown whether E2 and STX can modulate GABAB signaling in neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. We used single-cell RT-PCR and whole cell patch clamping with selective pharmacological reagents to show that NPY/AgRP cells of mice express the GABAB-R1 and -R2 Receptors and are hyperpolarized by the GABAB agonist baclofen in an E2-dependent manner. In males, E2 rapidly attenuated the coupling of GABAB Receptors to GIRKs, which was blocked by the general PI3K inhibitors wortmannin and LY-294002 or the selective p110β subunit inhibitor TGX-221. The ERα-selective agonist propyl pyrazole triol mimicked the effects of E2. STX, in contrast, enhanced the GABAB response in males, which was abrogated by the Estrogen Receptor (ER) antagonist ICI 182,780. In gonadectomized mice of both sexes, E2 enhanced or attenuated the GABAB response in different NPY/AgRP cells. Coperfusing wortmannin with E2 or simply applying STX always enhanced the GABAB response. Thus, in NPY/AgRP neurons, activation of the Gq-mER by E2 or STX enhances the GABAergic postsynaptic response, whereas activation of ERα by E2 attenuates it. These findings demonstrate a clear functional dichotomy of rapid E2 Membrane-initiated signaling via ERα vs. Gq-mER in a CNS neuron vital for regulating energy homeostasis.
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The Membrane Estrogen Receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17β-estradiol.
American journal of physiology. Endocrinology and metabolism, 2013Co-Authors: Arik W Smith, Oline K. Rønnekleiv, Martha A Bosch, Edward J Wagner, Martin J KellyAbstract:Besides its quintessential role in reproduction, 17β-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled Membrane Estrogen Receptor (Gq-mER) ligand STX rapidly increase...
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A selective Membrane Estrogen Receptor agonist maintains autonomic functions in hypoEstrogenic states.
Brain Research, 2013Co-Authors: Martin J Kelly, Oline K. RønnekleivAbstract:Abstract It is well known that many of the actions of Estrogens in the central nervous system are mediated via intracellular Receptor/transcription factors that interact with steroid response elements on target genes. But there is also a compelling evidence for the involvement of Membrane Estrogen Receptors in hypothalamic and other CNS functions. However, it is not well understood how Estrogens signal 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 Estrogens can rapidly alter neuronal activity within seconds, indicating that some cellular effects can occur via Membrane delimited events. In addition, Estrogens can affect second messenger systems including calcium mobilization and a plethora of kinases within neurons to alter cellular functions. Therefore, this brief review will summarize our current understanding of rapid Membrane-initiated and intracellular signaling by Estrogens in the hypothalamus, the nature of Receptors involved and how these Receptors contribute to maintenance of homeostatic functions, many of which go awry in menopausal states. This article is part of a Special Issue entitled Hormone Therapy .
Amy Christensen - One of the best experts on this subject based on the ideXlab platform.
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A Novel Membrane Estrogen Receptor Activated by STX Induces Female Sexual Receptivity through an Interaction with mGluR1a.
Neuroendocrinology, 2013Co-Authors: Amy Christensen, Paul E MicevychAbstract:Membrane initiated estradiol signaling has been shown to be vital for multiple physiological processes. Several Receptors have been proposed to mediate the actions of estradiol at the Membrane. Here, we examined the ability of STX, an agonist of a novel putative Membrane Estrogen Receptor, to activate sexually receptive behavior in the female rat. Infusions of STX into the arcuate nucleus of the hypothalamus resulted in the activation and internalization of μ-opioid Receptors in the medial preoptic nucleus, an action that is required for lordosis behavior. Indeed, STX was able to augment sexual receptivity in female rats given a sub-behavioral dose of estradiol. However, if the mGluR1a antagonist, LY367,385, was administered prior to STX, its circuit-activating effects, the internalization of μ-opioid Receptors, were lost. This suggests that the Receptor stimulated by STX activates rapid Membrane-initiated signaling through an interaction with mGluR1a – an effect previously described for Estrogen Receptor-α at the Membrane.
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cav1 sirna reduces Membrane Estrogen Receptor α levels and attenuates sexual receptivity
Endocrinology, 2012Co-Authors: Amy Christensen, Paul E MicevychAbstract:Although classic Estrogen Receptors (ER) have been proposed to mediate estradiol signaling, it has been relatively recently that mechanisms of trafficking these Receptors have been elucidated. ERα is palmitoylated and associates with caveolin proteins to be targeted to the cell Membrane. Caveolins are scaffold proteins that not only traffic ERα to the Membrane but also are involved in establishing metabotropic glutamate Receptor interactions that are necessary for activating G protein signaling. To demonstrate the role of caveolin proteins in regulating an estradiol-dependent behavior, sexual receptivity, we used small interfering RNA to knock down caveolin-1 (CAV1) expression in the arcuate nucleus of the hypothalamus. In CAV1 knockdown rats, Membrane, but not intracellular levels of ERα, were significantly reduced. As expected, Estrogenic stimulation of the arcuate nucleus of the hypothalamus to medial preoptic nucleus projection was abrogated in CAV1 knockdown rats, indicating that the Membrane-initiated activation of this circuit was compromised. Moreover, estradiol-induced lordosis behavior that is dependent on activation of μ-opioid Receptors in the medial preoptic nucleus was also significantly reduced. Thus, CAV1-mediated ERα trafficking to the cell Membrane is required for estradiol activation of circuits underlying female sexual receptivity.
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Membrane Estrogen Receptor α interactions with metabotropic glutamate Receptor 1a modulate female sexual receptivity in rats
The Journal of Neuroscience, 2007Co-Authors: Phoebe Dewing, Marissa I Boulware, Kevin Sinchak, Amy Christensen, Paul G Mermelstein, Paul E MicevychAbstract:In rats, female sexual behavior is regulated by a well defined limbic–hypothalamic circuit that integrates sensory and hormonal information. Estradiol activation of this circuit results in μ-opioid Receptor (MOR) internalization in the medial preoptic nucleus, an important step for full expression of sexual receptivity. Estradiol acts through both Membrane and intracellular Receptors to influence neuronal activity and behavior, yet the mechanism(s) and physiological significance of estradiol-mediated Membrane responses in vivo have remained elusive. Recent in vitro evidence found that stimulation of Membrane-associated Estrogen Receptor-α (ERα) led to activation of metabotropic glutamate Receptor 1a (mGluR1a). Furthermore, mGluR1a signaling was responsible for the observed downstream effects of estradiol. Here we present data that show that ERα and mGluR1a directly interact to mediate a rapid estradiol-induced activation of MOR in the medial preoptic nucleus, leading to female sexual receptivity. In addition, blockade of mGluR1a in the arcuate nucleus of the hypothalamus resulted in a significant attenuation of estradiol-induced MOR internalization, leading to diminished female sexual behavior. These results link Membrane-initiated estradiol actions to neural events modulating behavior, demonstrating the physiological importance of ERα-to-mGluR1a signaling.