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中国医师杂志 2012年第6期14卷 721-724页

作者：段军丛鲁红李刚易丽柯元南周益锋北京协和医学院研究生院北京100730 中日友好医院重症医学科急诊科心血管内科

目的研究可吸入颗粒物PM2.5对大鼠心脏交感神经分布的影响及其与心肌神经生长因子表达的关系，明确PM2.5是否具有致交感神经重构作用，探讨PM2.5致心律失常的可能机制。方法40只SD雄性大鼠，随机分为对照组和实验组，每组20只。实验组... 详细信息

目的研究可吸入颗粒物PM2.5对大鼠心脏交感神经分布的影响及其与心肌神经生长因子表达的关系，明确PM2.5是否具有致交感神经重构作用，探讨PM2.5致心律失常的可能机制。方法40只SD雄性大鼠，随机分为对照组和实验组，每组20只。实验组大鼠按25mg／kg剂量经气管内缓慢注入颗粒物悬液染毒，每周染毒2次，连续染毒4周；对照组以生理盐水代替颗粒物悬液；两组大鼠于末次染毒后次日处死，开胸留取双侧心耳和双心室前壁，通过免疫组化方法检测酪氨酸羟化酶染色阳性的交感神经纤维分布密度，同时采用蛋白免疫印迹法检测心肌神经生长因子（NGF）蛋白表达。结果与对照组比较，实验组大鼠吸人PM2.5后，心脏左室前壁和右室前壁交感神经分布密度明显升高（P〈0．01和P〈0．05），心肌NGF蛋白表达明显增加（P〈0．01和P〈0．05），两者密切相关。结论PM2.5能增加大鼠左右心室心肌细胞合成和分泌NGF蛋白，从而导致心室交感神经分布密度增加，证实具有致交感神经重构作用。

关键词：颗粒物/副作用心血管疾病/病因学心脏/神经支配交感神经系统/病理学神经生长因子/代谢

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Nerve growth factor signaling in caveolae-like domains at the plasma membrane

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第51期274卷 36707-36714页

作者： Huang, C Zhou, J Feng, AK Lynch, CC Klumperman, J DeArmond, SJ Mobley, WC Stanford Univ Dept Neurol & Neurol Sci Stanford CA 94305 USA Stanford Univ Dept Pediat Stanford CA 94305 USA Stanford Univ Neurosci Program Stanford CA 94305 USA Univ Calif San Francisco Neurosci Program San Francisco CA 94143 USA Univ Utrecht Sch Med NL-3584 CX Utrecht Netherlands Univ Calif San Francisco Dept Pathol San Francisco CA 94143 USA

Nerve growth factor (NGF) binding to its receptors TrkA and p75(NTR) enhances the survival, differentiation, and maintenance of neurons. Recent studies have suggested that NGF receptor activation may occur in caveolae or caveolae-like membranes (CLM). This is an intriguing possibility because caveolae have been shown to contain many of the signaling intermediates in the TrkA signaling cascade. To examine the membrane localization of TrkA and p75NTR, We isolated caveolae from 3T3-TrkA-p75 cells and CLM from PC12 cells. Immunoblot analysis showed that TrkA and p75NTR were enriched about 13- and 25-fold, respectively, in caveolae and CLM. Binding and cross-linking studies demonstrated that the NGF binding to both TrkA and p75NTR was considerably enriched in CLM and that about 90% of high affinity binding to TrkA was present in CLM. When PC12 cells were treated with NGF, virtually all activated (i.e. tyrosine phosphorylated) TrkA was found in the CLM. Remarkably, in NGF-treated cells, it was only in CLM that activated TrkA was coimmunoprecipitated with phosphorylated Shc and PLC gamma. These results document a signaling role for TrkA in CLM and suggest that both TrkA and p75(NTR) Signaling are initiated from these membranes.

关键词：细胞膜/代谢膜蛋白质类/代谢神经生长因子/代谢 PC12细胞磷酰化受体神经生长因子/代谢受体 trkA/代谢信号传导动物大鼠

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The prosegments of furin and PC7 as potent inhibitors of proprotein convertases -: In vitro and ex vivo assessment of their efficacy and selectivity

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第48期274卷 33913-33920页

作者： Zhong, M Munzer, JS Basak, A Benjannet, S Mowla, SJ Decroly, E Chrétien, M Seidah, NG Univ Montreal Clin Res Inst Montreal Biochem Lab Montreal PQ H2W 1R7 Canada Univ Montreal Clin Res Inst Montreal Lab Mol Neuroendocrinol Montreal PQ H2W 1R7 Canada Univ Montreal Clin Res Inst Montreal Prot Engn Network Ctr Excellence Montreal PQ H2W 1R7 Canada Ottawa Hosp Loeb Hlth Res Inst Prot Chem Ctr Ottawa ON K1Y 4K9 Canada Sch Med Ottawa ON K1Y 4K9 Canada

All proprotein convertases (PCs) of the subtilisin/kexin family contain an N-terminal prosegment that is presumed to act both as an intramolecular chaperone and an inhibitor of its parent enzyme. In this work, we examined inhibition by purified, recombinant bacterial prosegments of furin and PC7 on the in vitro processing of either the fluorogenic peptide pERTKR-MCA or the human immunodeficiency virus envelope glycoprotein gp160. These propeptides are potent inhibitors that display measurable selectivity toward specific proprotein convertases. Small, synthetic decapeptides derived from the C termini of the prosegments are also potent inhibitors, albeit less so than the full-length proteins, and the C-terminal P1 arginine is essential for inhibition. The bacterial, recombinant prosegments were also used to generate specific antisera, allowing us to study the intracellular metabolic fate of the prosegments of furin and PC7 expressed via vaccinia virus constructs. These vaccinia virus recombinants, along with transient transfectants of the preprosegments of furin and PC7, efficiently inhibited the ex vivo processing of the neurotrophins nerve growth factor and brain-derived neurotrophic factor. Thus, we have demonstrated for the first time that PC prosegments, expressed ex vivo as independent domains, can act in trans to inhibit precursor maturation by intracellular PCs.

关键词：氨基酸序列脑源性神经营养因子/遗传学脑源性神经营养因子/代谢 COS细胞细胞系电泳聚丙烯酰氨凝胶酶抑制剂/化学酶抑制剂/药理学费林蛋白酶基因表达质谱分析法分子序列数据神经生长因子/遗传学神经生长因子/代谢肽碎片/化学肽碎片/遗传学肽碎片/药理学蛋白质前体/遗传学蛋白质前体/代谢蛋白质加工转译后重组融合蛋白质类/分析重组融合蛋白质类/遗传学酿酒酵母菌/酶学敏感性与特异性序列同源性氨基酸枯草杆菌蛋白酶类/药物作用枯草杆菌蛋白酶类/遗传学枯草杆菌蛋白酶类/代谢肿瘤细胞培养的动物人类小鼠大鼠

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Simultaneous suppression of cdc2 and cdk2 activities induces neuronal differentiation of PC12 cells

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第17期275卷 12572-12580页

作者： Dobashi, Y Shoji, M Kitagawa, M Noguchi, T Kameya, T Kitasato Univ Sch Med Dept Pathol Kanagawa 2288555 Japan Kyushu Univ Med Inst Bioregulat Dept Mol & Cellular Biol Fukuoka 8128582 Japan Japan Sci & Technol Corp CREST Kawaguchi Saitama 3320012 Japan

The involvement of cdc2 and cdk2 during neuronal differentiation in rat pheochromocytoma PC12 cells was examined. When PC12 cells were cultured with nerve growth factor (NGF), expression of cdc2 decreased significantly after day 5, while expression of cdk2 decreased gradually after day 7. Cells overexpressing cdc2 or cdk2 were resistant to NGF-induced differentiation and growth suppression, and maintained high cdc2 or cdk2 kinase activity, respectively, during NGF treatment. In contrast, the NGF-treated parental cells showed a marked decline in these kinase activities after day 3. When PC12 cells were treated with specific inhibitors of cdc2/cdk2 (butyrolactone-I, olomoucin), they showed marked neurite extension and up-regulation of microtubule-associated protein 2 expression. In addition, treatment with mixtures of antisense oligonucleotides for cdc2 and cdk2 resulted in down-regulation of both cdc2 and cdk2 kinase activities as well as significant neurite outgrowth and up-regulation of microtubule-associated protein 2 expression. However, neurite outgrowth was not observed in cells treated with either single antisense oligonucleotide, or antisense cdc2 + cdk4 or cdk2 + cdk4 oligonucleotide mixtures. These results suggest that simultaneous down-regulation of cdc2 and cdk2 activity is sufficient and necessary for neuronal differentiation in PC12 cells.

关键词： CDC2蛋白激酶/拮抗剂和抑制剂 CDC2蛋白激酶/生理学 CDC2-CDC28激酶类细胞分化细胞分裂细胞周期蛋白依赖激酶2 细胞周期蛋白依赖激酶4 细胞周期蛋白质依赖激酶类/拮抗剂和抑制剂细胞周期蛋白质依赖激酶类/生理学光密度测定法免疫印迹法微管相关蛋白质类/代谢神经生长因子/代谢神经元/细胞学寡核苷酸类反义/代谢 PC12细胞磷酰化质粒沉淀素试验蛋白质丝氨酸苏氨酸激酶/拮抗剂和抑制剂蛋白质丝氨酸苏氨酸激酶/生理学原癌基因蛋白质类时间因素转染动物大鼠

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Nerve growth factor activation of nuclear factor κB through its p75 receptor is an anti-apoptotic signal in RN22 schwannoma cells

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第11期275卷 7558-7565页

作者： Gentry, JJ Casaccia-Bonnefil, P Carter, BD Vanderbilt Univ Sch Med Dept Biochem Nashville TN 37232 USA Vanderbilt Univ Sch Med Ctr Mol Neurosci Nashville TN 37232 USA NYU Med Ctr Skirball Inst Dept Mol Neurobiol New York NY 10012 USA

Recent evidence indicates that nerve growth factor (NGF) produces its effects through signaling contributions from both TrkA and the p75 receptor. In contrast to its trophic actions through TrkA, NGF binding to p75 has been shown to activate programmed cell death through a mechanism involving the stress kinase JNK. However, this receptor also activates nuclear factor kappa B (NF-kappa B), the role of which has yet to be determined. We investigated the function of p75-mediated NF-kappa B stimulation in regulating cell survival in the rat schwannoma cell line RN22, which expresses p75, but not TrkA Gel shift assays demonstrated activation of NF-kappa B in response to NGF within 30 min and lasting at least 4 h, NGF also stimulated JNK in the cells (detected by in vitro kinase assays) with a similar time course. Preventing activation of NF-kappa B with the specific inhibitor SN50 resulted in NGF-induced cell loss. Similarly, transfection of the cells with a mutant form of the endogenous NF-kappa B inhibitor (I kappa B alpha Delta N), which cannot be degraded and therefore remains bound to NF-kappa B, preventing its activation, resulted in a significant increase in the number of apoptotic cells following NGF treatment. These results suggest that NGF activation of NF-kappa B through the p75 receptor promotes survival, counterbalancing the pro-apoptotic signal.

关键词：细胞凋亡/生理学生物转运细胞核/代谢酶激活 JNK丝裂原活化蛋白激酶类丝裂原激活蛋白激酶类/代谢 NF-κB/拮抗剂和抑制剂 NF-κB/代谢神经生长因子/代谢神经鞘瘤/代谢肽类/药理学受体神经生长因子/代谢信号传导肿瘤细胞培养的动物大鼠

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Down-regulation of the neurotrophin receptor TrkB following ligand binding - Evidence for an involvement of the proteasome and differential regulation of TrkA and TrkB

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第12期275卷 8982-8990页

作者： Sommerfeld, MT Schweigreiter, R Barde, YA Hoppe, E Max Planck Inst Neurobiol Dept Neurobiochem D-82152 Planegg Martinsried Germany

This study examines the mechanisms by which the tyrosine kinase receptor TrkB is down-regulated following binding of brain-derived neurotrophic factor (BDNF). In primary cultures of cerebellar granule neurons, BDNF-induced reduction of TrkB receptors was largely prevented by the addition of specific proteasome inhibitors. HN10 cells, a neuronal cell line that can be readily transfected, also showed a marked down-regulation of cell surface TrkB following BDNF exposure. In addition, me observed that prolonged exposure to nerve growth factor of TrkA-transfected cells did not lead to the down-regulation seen with BDNF and TrkB. TrkA and TrkB chimeric molecules were therefore expressed in HN10 cells and tested for ligand-induced regulation. These experiments led to the conclusion that the motives responsible for down-regulation are contained in the cytoplasmic domain of TrkB, and a short sequence in the juxtamembrane domain of TrkB was identified that confers nerve growth factor-induced down-regulation when inserted into TrkA.

关键词：脑源性神经营养因子/代谢小脑/细胞学半胱氨酸内肽酶类/代谢半胱氨酸蛋白酶抑制剂/药理学减量调节配体多酶复合物/代谢突变神经生长因子/代谢神经元/生理学蛋白酶体内肽酶复合物蛋白质结合受体 trkA/代谢受体 trkB/生物合成受体 trkB/代谢受体 trkC/代谢重组融合蛋白质类/代谢动物大鼠

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Neuroprotective effects of LY379268, a selective mGlu2/3 receptor agonist: Investigations into possible mechanism of action in vivo

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第3期294卷 800-809页

作者： Bond, A Jones, NM Hicks, CA Whiffin, GM Ward, MA O'Neill, MF Kingston, AE Monn, JA Ornstein, PL Schoepp, DD Lodge, D O'Neill, MJ Eli Lilly & Co Ltd Lilly Res Ctr Windlesham GU20 6PH Surrey England Eli Lilly & Co Lilly Corp Ctr Indianapolis IN 46285 USA

The mechanisms underlying the neuroprotective effects of the group II metabotropic glutamate receptor (mGluR) agonist LY379268 were investigated in a gerbil model of global ischemia. LY379268 (10 mg/kg i.p.) 30 or 60 min after 5-min bilateral carotid artery occlusion (BCAO) attenuated the ischemia-induced hyperactivity and provided protection in the CA1 hippocampal cells. This neuroprotective effect was maintained (P <.001) when histological analysis was performed 14 and 28 days after BCAO. Furthermore, 24- or 48-h pretreatment with LY379268, 10 mg/kg i.p., before 5-min BCAO markedly reduced (P <.001 and P <.05, respectively) the damage to CA1 hippocampal neurons. This result is consistent with the induction of neuroprotective factors or a very long brain half-life. To study the possible induction of neuroprotective factors as contributing to this action of LY379268, brains were examined for expression of neurotrophic factors. Results indicated that LY379268 (16 mg/kg i.p.) failed to alter the expression of transforming growth factor-p, brain-derived neurotrophic factor, nerve growth factor, and basic fibroblast growth factor in the hippocampal regions of brains taken from gerbils sacrificed at 6, 24, 72, and 120 h postinjection. The new group II mGlu antagonist, LY341495, administered 1 h before 5-min BCAO, attenuated the neuroprotective effect of LY379268 administered 24 h before 5-min BCAO. Complementary pharmacokinetic studies showed that a significant receptor-active concentration persisted in the brain 24 h after LY379268 10 mg/kg i.p. We conclude that group II mGluR occupancy, rather than induction of neuroprotective factors, explains the long-lasting neuroprotective effect of LY379268 in the gerbil model of global ischemia.

关键词：氨基酸类/药理学动脉闭塞性疾病/并发症二环化合物杂环/药理学脑缺血/药物疗法脑缺血/病因学脑缺血/代谢脑缺血/病理生理学脑源性神经营养因子/代谢颈动脉疾病/并发症兴奋性氨基酸激动剂/药理学沙鼠亚科海马/药物作用海马/病理学免疫组织化学运动活动/药物作用神经生长因子/代谢神经元/病理学神经保护药/药理学受体亲代谢性谷氨酸盐/激动剂转化生长因子β/代谢动物男(雄)性

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Developmental profiles of growth-associated protein (Gap43), Ngfb, Bndf and Ntf4 mRNA levels in the rat forebrain after exposure to 60 Hz magnetic fields

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RADIATION RESEARCH 2000年第5期153卷 642-647页

作者： Harry, GJ Bartenbach, M Haines, W Bruccoleri, A NIEHS Neurotoxicol Grp Res Triangle Pk NC 27709 USA

Fischer 344 rats were exposed to 60 Hz magnetic fields (EMFs) during gestation and lactation. Rats received continuous exposure to 2-, 200- or 1000-mu T magnetic fields for 18.5 h per day, 7 days a week, or sham exposure (sham controls). During postnatal development, on postnatal days 1, 3, 6, 9, 15 and 20, forebrain tissue from male pups was examined for alterations in mRNA level for developmentally regulated central nervous system-specific proteins. Alterations in these factors during critical periods of development could result in alterations in the final neural network. Gap43 (growth-associated protein 43) mRNA was measured by Northern hybridization as a developmental indicator of axonal growth during the development of the neuron. Between postnatal days 1 and 9, detectable levels of Gap43 mRNA displayed a similar pattern across all sham control and exposure groups. In addition to Gap43, mRNA levels for the nervous system-specific growth factors ciliary neurotrophic factor (Cntf), brain-derived neurotrophic factor (Bdnf), beta nerve growth factor (Ngfb), neurotrophin-3 (Ntf3), and neurotrophin-4 (Ntf4) were examined by RNase protection assay. While there is public concern for developmental neurotoxicity associated with exposure to EMFs, these data, generated from animals exposed to 2-, 200 or 1000-mu T magnetic fields during both gestational and lactational periods of development, suggest that under these conditions no significant alterations in these critical factors for brain development occur. (C) 2000 by Radiation Research Society.

关键词：动物新生动物吮乳期脑源性神经营养因子/遗传学脑源性神经营养因子/代谢剂量效应关系辐射电磁场/副作用环境暴露/副作用 GAP-43蛋白/遗传学 GAP-43蛋白/代谢胶质细胞源性神经营养因子母亲暴露/副作用神经生长因子/遗传学神经生长因子/代谢神经生长因子类/遗传学神经生长因子类/代谢神经组织蛋白质类/遗传学神经组织蛋白质类/代谢神经营养因子3/遗传学神经营养因子3/代谢前脑/生长和发育前脑/代谢前脑/辐射效应 RNA 信使/分析大鼠近交F344 大鼠 Sprague-Dawley 核糖核酸酶类/代谢动物女(雌)性男(雄)性大鼠

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Solid-phase syntheses of β-turn analogues to mimic or disrupt protein-protein interactions

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ACCOUNTS OF CHEMICAL RESEARCH 2001年第10期34卷 826-835页

作者： Burgess, K Texas A&M Univ Dept Chem College Stn TX 77842 USA

Protein-protein interactions are difficult targets in medicinal chemistry, but they will become increasingly important as data from The Human Genome Project is interpreted. Our work focuses on beta -turn mimics that are designed to mimic or disrupt some of these interactions. Solid-phase syntheses and preferred conformations of beta -turn mimics that incorporate dipeptide units are discussed. The activity of one illustrative compound that potentiates the interaction of the nerve growth factor with its transmembrane tyrosine kinase receptor TrkA is outlined. Finally, the importance of dimeric turn mimics and some new approaches to these are described.

关键词：分子模拟神经生长因子/化学神经生长因子/代谢寡肽类/化学合成肽库蛋白质结构二级蛋白质类/化学受体 trkA/化学受体 trkA/代谢人类

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NRAGE, a novel MAGE protein, interacts with the p75 neurotrophin receptor and facilitates nerve growth factor-dependent apoptosis

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NEURON 2000年第2期27卷 279-288页

作者： Salehi, AH Roux, PP Kubu, CJ Zeindler, C Bhakar, A Tannis, LL Verdi, JM Barker, PA McGill Univ Montreal Neurol Inst Ctr Neuronal Survival Montreal PQ H3A 2B4 Canada John P Robarts Res Inst London ON N6A 5K8 Canada

The mechanisms employed by the p75 neurotrophin receptor (p75NTR) to mediate neurotrophin-dependent apoptosis are poorly defined. Two-hybrid analyses were used to identify proteins involved in p75NTR apoptotic signaling, and a p75NTR binding partner termed NRAGE (for (n) under bar eurotrophin (r) under bar eceptor-interacting M (A) under bar (G) under bar (E) under bar homolog) was identified. NRAGE binds p75NTR in vitro and in vivo, and NRAGE associates with the plasma membrane when NGF is bound to p75NTR. NRAGE blocks the physical association of p75NTR with TrkA, and, conversely, TrkA overexpression eliminates NRAGE-mediated NGF-dependent death, indicating that interactions of NRAGE or TrkA with p75NTR are functionally and physically exclusive. NRAGE over-expression facilitates cell cycle arrest and permits NGF-dependent apoptosis within sympathetic neuron precursors cells. Our results show that NRAGE contributes to p75NTR-dependent cell death and suggest novel functions for MAGE family proteins.

关键词：肾上腺素能纤维/代谢抗原肿瘤细胞凋亡/生理学脑/胚胎学脑/代谢细胞区室化细胞周期/遗传学细胞膜/代谢克隆分子 DNA结合蛋白质类/代谢黑素瘤特异性抗原分子序列数据肿瘤蛋白质类/遗传学神经生长因子/代谢器官特异性 RNA 信使/生物合成受体神经生长因子/代谢受体 trkA/代谢序列分析 DNA 序列同源性氨基酸信号传导/遗传学脊髓/胚胎学脊髓/代谢双杂交系统技术动物人类大鼠

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