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The tyrosine kinase and mitogen-activated protein kinase pathways mediate multiple effects of estrogen in hippocampus

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PROCEEdInGS OF THE nATIOnAL ACAdEMY OF SCIEnCES OF THE UnITEd STATES OF AMERICA 2000年第7期97卷 3602-3607页

作者： Bi, RF Broutman, G Foy, MR Thompson, RF Baudry, M Univ So Calif Neurosci Program Los Angeles CA 90089 USA Loyola Marymount Univ Dept Psychol Los Angeles CA 90045 USA

Estrogen replacement therapy in women is associated with improvement of cognitive deficits and reduced incidence of Alzheimer's disease. The present study indicates that estrogen is neuroprotective against n-methyl-d-aspartate (nMdA)- and kainate-mediated neurotoxicity, an effect mediated by tyrosine kinase/mitogen-activated protein kinase (MAPK) pathways. Estrogen also stimulates tyrosine phosphorylation of nMdA receptors via an src tyrosine kinase/MAPK pathway. Finally, estrogen-mediated enhancement of long-term potentiation in hippocampal slices is mediated by activation of an src tyrosine kinase pathway. Thus, estrogen, by activating an src tyrosine kinase and the extracellular signal-related protein kinase/MAPK signaling pathway, both enhances nMdA receptor function and long-term potentiation and retains neuroprotective properties against excitotoxicity. These findings warrant further evaluation of the usefulness of estrogenic compounds for the treatment of Alzheimer's disease and other neurodegenerative diseases.

关键词：动作电位阿尔茨海默病/药物疗法雌激素类/药理学雌激素类/治疗应用海马/药物作用海马/酶学海马/代谢海马/生理学 MAP激酶信号系统磷酰化蛋白酪氨酸激酶类/代谢受体 n-甲基-d-天冬氨酸/拮抗剂和抑制剂受体 n-甲基-d-天冬氨酸/代谢动物大鼠

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Alterations in subunit expression, composition, and phosphorylation of striatal n-methyl-d-aspartate glutamate receptors in a rat 6-hydroxydopamine model of Parkinson's disease

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MOLECULAR PHARMACOLOGY 2000年第2期57卷 342-352页

作者： dunah, AW Wang, YH Yasuda, RP Kameyama, K Huganir, RL Wolfe, BB Standaert, dG Massachusetts Gen Hosp Dept Neurol Boston MA 02114 USA Harvard Univ Sch Med Boston MA USA Georgetown Univ Sch Med Dept Pharmacol Washington DC USA Johns Hopkins Univ Med Ctr Dept Neurosci Baltimore MD 21218 USA

Recent evidence has linked striatal n-methyl-d-aspartate (nMdA) receptor function to the adverse effects of long-term dopaminergic treatment in Parkinson's disease. We have studied the abundance, composition, and phosphorylation of nMdA receptor subunits (nRs) in the rat 6-hydroxydopamine lesion model of parkinsonism. In lesioned striatum, the abundance of nR1 and nR2B in striatal membranes was decreased to 68 +/- 3.2 and 62 +/- 4.4%, respectively, relative to the unlesioned striata, whereas the abundance of nR2A was unchanged. Coimmunoprecipitation of nMdA receptors under nondenaturing conditions revealed that these changes reflected a selective depletion of receptors composed of nR1/nR2B, without alteration in receptors composed of nR1/nR2A. However, the abundance and composition of striatal nMdA receptors in extracts containing both cytoplasmic and membrane proteins were not altered in lesioned rats, suggesting that the changes in the membrane fraction resulted from intracellular redistribution of receptors. The phosphorylation of nR1 protein at serine 890 and serine 896, but not at serine 897, and the tyrosine phosphorylation of nR2B but not nR2A were decreased in the membrane fraction of the lesioned striatum. Chronic treatment of lesioned rats with L-dopa normalized the alterations in the abundance and subunit composition of the nMdA receptors in striatal membranes, and produced striking hyperphosphorylation, both of nR1 at serine residues, and nR2A and nR2B at tyrosine residues. These findings suggest that the adverse motor effects of chronic L-dopa therapy may result from alterations in regulatory phosphorylation sites on nMdA receptors.

关键词：抗震颤麻痹药/药理学细胞膜/药物作用细胞膜/代谢纹状体/药物作用纹状体/代谢疾病模型动物左旋多巴/药理学神经元/药物作用神经元/代谢羟多巴胺帕金森病继发性/化学诱导帕金森病继发性/代谢磷酰化大鼠 Sprague-dawley 受体 n-甲基-d-天冬氨酸/药物作用受体 n-甲基-d-天冬氨酸/代谢动物男(雄)性大鼠

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Translocation of glutamate transporter subtype excitatory amino acid carrier 1 protein in kainic acid-induced rat epilepsy

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AMERICAn JOURnAL OF PATHOLOGY 2003年第2期163卷 779-787页

作者： Furuta, A noda, M Suzuki, SO Goto, Y Kanahori, Y Rothstein, Jd Iwaki, T Kyushu Univ Dept Neuropathol Grad Sch Med Sci Fukuoka 812 Japan Kyushu Univ Dept Clin Neurophysiol Grad Sch Med Sci Fukuoka 812 Japan Kyushu Univ Neurol Inst Grad Sch Med Sci Fukuoka 812 Japan Kyushu Univ Lab Pathophysiol Grad Sch Pharmaceut Sci Fukuoka 812 Japan Johns Hopkins Univ Sch Med Dept Neurol Baltimore MD 21205 USA Johns Hopkins Univ Sch Med Dept Neurosci Baltimore MD 21205 USA

Glutamate excitotoxicity has been implicated in the pathophysiology of epilepsy. Systemic injection of kainic acid (KA) in the rat produces an animal model of human temporal lobe epilepsy. We examined the temporal expression of the sodium-dependent neuronal glutamate transporter, excitatory amino acid carrier 1 (EAAC1), in KA-induced rat epilepsy. As an early alteration, perinuclear deposits of EAAC1 protein were found mainly in the large pyramidal neurons at the hippocampus, neocortex, piriform cortex, and amygdala with the reduction of neuropil staining 6 hours after KA injection. Immunoelectron microscopic study revealed that the perinuclear EAAC1 immunoreactivity corresponded to the translocation to the Golgi complex. At this time point, EAAC1 mRnA was down-regulated. The intracellular aggregation of EAAC1 primarily disappeared by 24 hours. In vitro studies indicated that internalization of EAAC1 from the plasma membrane to the intracellular compartment by KA treatment was associated with the reduction of electrogenic transporter currents. Our results suggest that the transient EAAC1 internalization participates in the modulation of the transporter function preventing excessive glutamate uptake to pyramidal neurons during the early stage of epilepsy.

关键词：氨基酸转运系统X-AG/代谢细胞系疾病模型动物癫痫/化学诱导癫痫/代谢兴奋性氨基酸激动剂/毒性兴奋性氨基酸转运体3 谷氨酸质膜转运蛋白质类谷氨酸/代谢红藻氨酸神经元/细胞学神经元/代谢膜片钳术大鼠 Wistar 受体 AMPA/代谢受体 n-甲基-d-天冬氨酸/代谢协同转运子/代谢动物人类男(雄)性大鼠

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Attenuation of nMdA receptor activity and neurotoxicity by nitroxyl anion, nO^-

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nEUROn 1999年第2期24卷 461-469页

作者： Kim, WK Choi, YB Rayudu, PV das, P Asaad, W Arnelle, dR Stamler, JS Lipton, SA Brigham & Womens Hosp Cerebrovasc & Neurosci Res Inst Boston MA 02115 USA Harvard Univ Sch Med Program Neurosci Boston MA 02115 USA Duke Univ Med Ctr Howard Hughes Med Inst Dept Med Durham NC 27710 USA Duke Univ Med Ctr Dept Cell Biol Durham NC 27710 USA

Recent evidence indicates that the nO-related species, nitroxyl anion (nO-), is produced in physiological systems by several redox metal-containing proteins, including hemoglobin, nitric oxide synthase (nOS), superoxide dismutase, and S-nitrosothiols (SnOs), which have recently been identified in brain. However, the chemical biology of nO- remains largely unknown. Here, we show that nO--unlike nO., but reminiscent of nO+ transfer (or S-nitrosylation) - reacts mainly with Cys-399 in the nR2A subunit of the n-methyl-d-aspartate (nMdA) receptor to curtail excessive Ca2+ influx and thus provide neuroprotection from excitotoxic insults. This effect of nO- closely resembles that of nOS, which also downregulates nMdA receptor activity under similar conditions in culture.

关键词：阴离子/代谢细胞培养的大脑皮质/细胞学 n-甲基天冬氨酸/药理学神经元/代谢神经毒素类/代谢一氧化氮/药理学一氧化氮供体/药理学一氧化氮合酶/代谢氧化氮类/代谢卵母细胞大鼠 Sprague-dawley 受体 n-甲基-d-天冬氨酸/化学受体 n-甲基-d-天冬氨酸/药物作用受体 n-甲基-d-天冬氨酸/代谢受体 n-甲基-d-天冬氨酸/生理学巯基化合物/化学巯基化合物/代谢光滑爪蟾动物女(雌)性大鼠

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A new form of long-term depression in the perirhinal cortex

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nATURE nEUROSCIEnCE 2000年第2期3卷 150-156页

作者： Cho, K Kemp, n noel, J Aggleton, JP Brown, MW Bashir, ZI Univ Bristol Dept Anat MRC Ctr Synapt Plast Bristol BS8 1TD Avon England Univ Nice Sophia Antipolis Fac Sci F-06108 Nice France Cardiff Univ Sch Psychol Cardiff CF10 3YJ S Glam Wales

We demonstrate a form of long-term depression (LTd) in the perirhinal cortex that relies on interaction between different glutamate receptors. Group II metabotropic glutamate (mGlu) receptors facilitated group 1 mGlu receptor-mediated increases in intracellular calcium. This facilitation plus nMdA receptor activation may be necessary for induction of LTd at resting membrane potentials. However, depolarization enhanced nMdA receptor function and removed the requirement of synergy between group I and group II mGlu receptors: under these conditions, activation of only nMdA and group I mGlu receptors was required for LTd. Such glutamate receptor interactions potentially provide new rules for synaptic plasticity. These forms of LTd occur in the perirhinal cortex, where long-term decreases in neuronal responsiveness may mediate recognition memory.

关键词：受体 n-甲基-d-天冬氨酸/拮抗剂和抑制剂受体 n-甲基-d-天冬氨酸/代谢突触传递/药物作用突触传递/生理学颞叶/细胞学颞叶/代谢时间

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Early postnatal switch in magnesium sensitivity of nMdA receptors in rat CA1 pyramidal cells

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JOURnAL OF PHYSIOLOGY-LOndOn 1999年第1期521卷 99-111页

作者： Kirson, Ed Schirra, C Konnerth, A Yaari, Y Hebrew Univ Jerusalem Hadassah Fac Med Inst Med Sci Dept Physiol IL-91120 Jerusalem Israel Univ Saarland Inst Physiol 1 D-66421 Homburg Germany

1. Whole-cell patch-damp recordings of iontophoretically induced n-methyl-d-aspartate (nMdA) receptor-mediated currents (I-nMdA) in CA1 pyramidal cells in hippocampal slices from 1- to 40-day-old rats were used to characterize developmental changes in the Mg2+ sensitivity of nMdA receptors. 2. The dose-response relations for extracellular Mg2+ blockade of I-nMdA indicated a high affinity binding of Mg2+ to nMdA receptors at membrane potentials more negative than -60 mV, independent of postnatal age. 3. depolarizing the cells unblocked nMdA receptors by decreasing their affinity for Mg2+. The efficacy of depolarization in unblocking nMdA receptors markedly increased after postnatal day 4 (P4), endowing the receptors with a greater voltage dependence. 4. The nR2B subunit-specific nMdA antagonist ifenprodil reduced I-nMdA in pyramidal cells of all ages. The sensitivity of I-nMdA to ifenprodil was greatest during the first postnatal week and decreased thereafter, indicating an enhanced contribution of nR2B subunit-containing nMdA receptors to I-nMdA in the first week after birth. 5. In the first postnatal week, the ifenprodil-insensitive InMdA component had a lower voltage dependence than the total I-nMdA. In older pyramidal cells, the voltage dependence of the ifenprodil-insensitive component and the total I-nMdA were similar. 6. In another set of CA1 pyramidal cells, single-cell reverse transcription and polymerase chain reaction (RT-PCR) were used to characterize concomitant developmental changes in nMdA subunit mRnA expression. The mRnA for the nR2d subunit was detected during the first postnatal week in 50% of the cells and disappeared thereafter. The proportion of cells expressing the nR2A and nR2B subunits remained relatively constant throughout the first five postnatal weeks. 7. We conclude that nMdA receptors in hippocampal CA1 pyramidal cells are effectively blocked by Mg2+ at all ages. After 4 days they become much less sensitive to Mg2+ at depolarized membra

关键词：动物新生基因表达调控发育期海马/细胞学海马/生长和发育海马/代谢镁/药理学膜电位膜片钳术哌啶类/药理学蛋白质结构四级锥体细胞/药物作用锥体细胞/代谢 RnA 信使/遗传学 RnA 信使/代谢大鼠 Wistar 受体 n-甲基-d-天冬氨酸/药物作用受体 n-甲基-d-天冬氨酸/遗传学受体 n-甲基-d-天冬氨酸/代谢逆转录聚合酶链反应动物大鼠

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Insulin-induced oxidative neuronal injury in cortical culture:: Mediation by induced n-methyl-d-aspartate receptors

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IUBMB LIFE 1999年第3期48卷 263-269页

作者： noh, KM Lee, JC Ahn, YH Hong, SH Koh, JY Univ Ulsan Coll Med Natl Creat Res Initiat Ctr Study CNS Zinc Songpa Gu Seoul 137040 South Korea Univ Ulsan Coll Med Dept Neurol Songpa Gu Seoul 137040 South Korea Seoul Natl Univ Dept Mol Biol Seoul South Korea Seoul Natl Univ Inst Mol Biol & Genet Seoul South Korea

While effectively attenuating neuronal apoptosis in mouse cortical culture, insulin paradoxically induced neuronal necrosis with 48 h of exposure, The insulin neurotoxicity was blocked by an antioxidant but not by caspase inhibitors. Exposure to insulin led to tyrosine phosphorylation of the insulin receptor and the insulin-like growth factor-1 (IGF-1) receptor and activation of protein kinase C (PKC) and phosphoinositide 3-kinase (PI3-kinase), Inhibitors of tyrosine kinase and PKC, but not PI3-kinase, attenuated the insulin neurotoxicity. Conversely, the inhibitor of PI3-kinase but not PKC reversed the antiapoptotic effect of insulin. Suggesting that the gene activity-dependent emergence of excitotoxicity contributed to insulin neurotoxicity, macromolecule synthesis inhibitors and n-methyl-d-aspartate (nMdA) antagonists blocked it, Consistently, exposure to insulin increased the level of the nR2A subunit of the nMdA receptor without much altering nR1 or nR2B levels. The present study suggests that insulin can be both neuroprotective and neurotoxic in the same cell system but by way of different signaling cascades.

关键词： 1-磷脂酰肌醇3-激酶/代谢细胞培养的大脑皮质/代谢大脑皮质/病理学降血糖药/毒性胰岛素/毒性神经元/代谢神经元/病理学氧化性应激受体 IGF1型/代谢受体胰岛素/代谢受体 n-甲基-d-天冬氨酸/代谢信号传导/药物作用动物小鼠

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Slow deactivation kinetics of nMdA receptors containing nR1 and nR2d subunits in rat cerebellar Purkinje cells

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JOURnAL OF PHYSIOLOGY-LOndOn 2000年第2期525卷 299-305页

作者： Misra, C Brickley, SG Wyllie, dJA Cull-Candy, SG UCL Dept Pharmacol London WC1E 6BT England Univ Edinburgh Dept Neurosci Edinburgh EH8 9JZ Midlothian Scotland

1. We have examined the deactivation kinetics of native Iv-methyl-d-aspartate receptors (nMdARs) containing nR1 and nR2d subunits by patch-clamp recording from Purkinje cells in cerebellar slices from young rats. 2. nMdAR-mediated whole-cell currents were elicited in response to bath application of 20 mu M nMdA and 50 mu M glycine. The nMdAR-mediated currents were small, with an average whole-cell conductance of approximately 750 pS. 3. Following the rapid application of brief pulses (1-10 ms) of 1 mM glutamate to outside-out membrane patches, we observed a low-conductance type of single-channel activity which lasted up to 30 s after the removal of agonist. 4. Analysis of individual channel openings revealed asymmetry of transitions between the main- and subconductance states - a characteristic of nR1/nR2d-containing nMdARs. The averaged macroscopic current exhibited a decay time course which was well described by a single exponential function with a time constant of similar to 3 s. 5. We conclude that native nR1/nR2d-containing nMdARs, like their recombinant counterparts, display very slow deactivation kinetics. This feature should provide a means for identification of these receptors at synapses, and indicates that they do not contribute to the synaptic nMdAR currents so far described.

关键词：谷氨酸/药理学动力学膜片钳术浦肯野细胞/药物作用浦肯野细胞/代谢大鼠 Sprague-dawley 受体 n-甲基-d-天冬氨酸/拮抗剂和抑制剂受体 n-甲基-d-天冬氨酸/化学受体 n-甲基-d-天冬氨酸/代谢动物大鼠

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The trapping block of nMdA receptor channels in acutely isolated rat hippocampal neurones

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JOURnAL OF PHYSIOLOGY-LOndOn 2000年第3期526卷 493-506页

作者： Sobolevsky, AI Yelshansky, MV Russian Acad Med Sci Inst Gen Pathol & Pathol Physiol Moscow 125315 Russia

1. n-methyl-d-aspartate (nMdA) receptor responses were recorded from acutely isolated rat hippocampal neurones using the whole-cell patch-clamp, technique. A rapid perfusion system was used to study the voltage-dependent block of nMdA channels by Mg2+, amantadine (AM) and n-2-(adamantyl)-hexamethylenimine (A-7). 2. Mg2+, AM and A-7-induced stationary blockade of nMdA channels increased with the blocker concentration but did not depend on the agonist (aspartate;Asp) concentration. Blockade by AM and A-7, but not Mg2+, was weakly use dependent. 3. 'Hooked' tail currents were observed after coapplication of Asp and Mg2+, AM or A-7. The hooked tail current kinetics, amplitude and carried charge indicated that Mg2+, AM and A-7 did not prevent closure and desensitization of nMdA channels nor agonist dissociation. 4. Tail currents following Asp application in the absence and continuous presence of Mg2+, AM or A-7 had similar kinetics. 5. Application of multiple stationary and kinetic criteria to the Mg2+, AM and A-7 blockade led us to conclude that their effects on nMdA channels can be described in terms of a 'trapping' model, which is fully symmetrical with respect to the blocking transition. 6. In general, the apparent blocking/recovery kinetics predicted by the fully symmetrical trapping model differ significantly from the microscopic kinetics and depend on the rate of binding and unbinding of the blocker, the nMdA channel open probability and the rate of solution exchange.

关键词：金刚烷/类似物和衍生物金刚烷/药理学金刚烷胺/代谢金刚烷胺/药理学抗震颤麻痹药/药理学天冬氨酸/代谢天冬氨酸/药理学细胞分离多巴胺药/药理学剂量效应关系药物海马/细胞学海马/药物作用海马/代谢离子通道/药物作用离子通道/代谢镁/代谢镁/药理学膜电位/药物作用神经元/细胞学神经元/药物作用神经元/代谢膜片钳术灌流大鼠 Wistar 受体 n-甲基-d-天冬氨酸/激动剂受体 n-甲基-d-天冬氨酸/拮抗剂和抑制剂受体 n-甲基-d-天冬氨酸/代谢动物大鼠

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The modulatory effect of spermine on the glutamate-nMdA receptor is regionally variable in normal human adult cerebral cortex

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PHARMACOLOGY & TOXICOLOGY 1999年第3期84卷 135-142页

作者： Mortensen, M Matsumoto, I niwa, S dodd, PR Univ Queensland Dept Biochem Brisbane Qld 4072 Australia Fukushima Med Coll Dept Neuropsychiat Fukushima Japan

The MK-801, glutamate and polyamine binding sites on the n-methyl-d-aspartate class of glutamate receptors labelled with [H-3]MK-801 were characterized in four cortical areas (sensorimotor, superior temporal, mid-frontal and occipital) from seven human adult control cases. Age, post-mortem delay, tissue storage time and sex had no significant effects on any of the parameters measured. dissociation constants (K-d values) for MK-801 showed similar mean values in the four cortical areas, whereas receptor densities (B-max values) showed significant differences between sensorimotor or occipital and superior temporal or mid-frontal cortex, There were marked regional differences in the profiles of the spermine- and glutamate-incremented enhancement of specific [H-3]MK-801 binding. The EC50 for the glutamate enhancement was significantly higher in the occipital than in the mid-frontal and sensorimotor cortex, whereas maximal glutamate-enhanced binding values did not differ. The maximal enhancement of [H-3]MK-801 binding by spermine and glutamate varied between the cases, ranging from zero to 40.4+/-9.3 fmol . mg protein(-1) for spermine, and from 85+/-5 to 111+/-10 fmol . mg protein(-1) for glutamate. Maximal spermine enhancement of [H-3]MK-801 binding was significantly more variable in superior temporal or mid-frontal than in sensorimotor or occipital cortex. The results suggest that n-methyl-d-aspartate receptor sites, especially the polyamine site, are heterogeneous in human cerebral cortex, and show a high degree of regional and individual variability.

关键词：年龄因素尸体解剖结合部位大脑皮质/代谢地卓西平马来酸盐/代谢谷氨酸/药理学配体聚胺类/代谢受体谷氨酸/药物作用受体谷氨酸/代谢受体 n-甲基-d-天冬氨酸/药物作用受体 n-甲基-d-天冬氨酸/代谢性别因素精胺/药理学时间因素老年人女(雌)性人类男(雄)性

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