p75神经营养因子受体在脑缺血后神经元凋亡中的作用

p75神经营养因子受体(p75 neurotrophin receptor, p75 NTR)为肿瘤坏死因子受体超家族成员,通过与原肌球蛋白受体激酶(tropomyosin receptor kinase, Trk)受体相互作用或与神经营养因子结合,介导多种复杂的信号转导通路,诱导突触生长和影响细胞存亡。急性...     

原肌球蛋白相关激酶与脑缺血

脑缺血损伤时,神经营养因子与其特异性受体原肌球蛋白相关激酶(Trk)结合而对缺血神经元起保护作用.Trk的激活模式及其与脑缺血关系的研究有重要意义.文章就,Trk的生物学特性、作用途径、与脑缺血的关系及应用前景做了综述.     

神经营养因子家族受体与信号转导的研究现状

神经营养因子家族是一类重要的神经营养因子,其受体包括Trk和p75受体,这两类受体通过引发不同的信号转导途径发挥不同的,有时甚至是相反的生物学效应。两类受体之间又存在复杂的相互作用,共同调节神经元的发生、存活、损伤、修复和死亡。     

脑源性神经营养因子——酪氨酸激酶受体B蛋白通路参与血管动脉粥样硬化的形成

脑源性神经营养因子与其高亲和力受体酪氨酸激酶受体B,不仅参与神经元的生成、分化、维持和损伤修复等生理和病理功能,而且也在动脉内皮功能的完整性中起着关键的作用。现整合近年文献,通过对其结构、特点、功能等进行分析,探讨脑源性神经营养因子——酪氨酸激酶受体B通路在动脉内皮中的作用,阐明其在动脉粥样硬化形成中的生理学意义。     

神经营养因子受体的研究进展

神经营养因子家族在神经细胞的生长发育、保护修复过程中起着极其重要的作用.而神经营养因子受体是启动信号转导,产生生物学效应的重要物质.根据同源性大小、基因表达部位和蛋白作用的专一性以及信号传递机制的不同,可将神经营养因子分为三个家族:神经生长因子家族、睫状神经营养因子家族和胶质细胞源性神经营养因子.本文从结构、功能、信号传递机制等方面,对其相应受体的最新研究进展作一综述.     

芍药苷对大鼠皮质酮损伤的海马神经元TrkB/BDNF信号通路的影响

目的观察芍药苷对皮质酮诱导海马神经元损伤的影响。方法体外培养新生SD大鼠海马神经元,采用皮质酮诱导原代培养海马神经元建立皮质酮损伤模型。培养体系中加入不同浓度的芍药苷进行预处理。采用WST-1法检测芍药苷对神经元存活率的影响,应用PCR与Western印迹检测神经元脑源性神经营养因子(BDNF)与酪氨酸激酶受体B(Trk B)的表达。结果与皮质酮组相比,中高剂量芍药苷可明显增加海马神经元活力(P0.05),可明显增加海马神经元Trk B与BDNF的mRNA与蛋白表达水平(P0.05)。结论芍药苷对皮质酮诱导的原代培养海马神经元损伤具有保护作用,具有抗抑郁作用。     

BDNF对食管癌细胞株ECa9706体外侵袭能力的影响

目的:本研究观察脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)对食管癌细胞株ECa9706体外增殖和迁移能力的影响以及机制.方法:采用MTT和Transwell方法分别观察BDNF以及酪氨酸激酶受体B(tyrosine kinase receptor B,Trk B)抑制剂K252a对ECa9706细胞增殖和迁移能力的影响,采用实时定量聚合酶链反应(real-time quantitative polymerase chain reaction,q PCR)和Western blot方法分别检测ECa9706细胞中Trk B和磷脂酶C(phospholipase C,PLC)-γ1的m RNA和蛋白表达水平.结果:BDNF可显著促进ECa9706细胞增殖和迁移能力,该作用可被K252a拮抗.与对照组相比,BDNF可诱导Trk B的m RNA和蛋白表达显著增加,并提高PLC-γ1的蛋白表达水平.结论:BDNF/Trk B/PLC-γ1在食管癌细胞迁移浸润中具有重要作用.     

脑源性神经生长因子在非小细胞肺癌细胞侵袭转移中的作用

1995年全世界就有60万人死于肺癌,而且每年人数都处于上升的趋势,其中女性患肺癌的发生率在性别中的比重上升明显〔1〕。脑源性神经生长因子(BDNF)属于神经营养因子家族,BDNF通过与受体酪氨酸激酶受体B结合,激活细胞内的酪氨酸激酶信号通路,促进抑制细胞失巢凋亡能力,还可以促进肿瘤细胞的生存,在肿瘤生长、浸润和转移的过程中发挥重     

P75NTR的研究进展

Ｐ７５＾ＮＴＲ是神经营养素的低亲和力受体，近年来研究认为砣具有逆行转输神经营养素选择相应的神经营养素、调节神经营养因子的酷氨酸激酶受体的信号传递和介导细胞凋亡等方面的功能。另外Ｐ７５＾ＭＴＲ与ＴｒＫＡ之间存在着相互抑制的关系。而且有人认为脑内Ｔｒｋｓ表达和功能异常及其与Ｐ７５＾ＮＴＲ的关系失衡可能对阿尔茨海默病的病理发展起重要的作用。     

β-神经生长因子在脑缺血神经保护中作用机制的研究

目的 观察脑缺血后原肌球蛋白受体激酶(Trk)和蛋白激酶B(Akt)信号蛋白的动态变化规律,同时观察β-神经生长因子(β-NGF)对其影响,探讨β-NGF脑缺血保护的作用机制. 方法制作大鼠局灶性脑缺血模型,腹腔注射β-NGF,应用免疫组化和Western印迹法检测Trk及Akt磷酸化的变化. 结果缺血8 h后Trk受体在半暗带表达增加.缺血2 h后Trk磷酸化即丌始不断增加,Akt的磷酸化则先减少,后逐渐恢复,其中缺血8 h较正常对照组减少了76.5%(P<0.01).注射β-NGF后在缺血12 h,Trk磷酸化水平增加了 74.4%(P<0.01);Akt磷酸化水平在缺血8 h时明显恢复,在24 h 与正常对照组比较差异无统计学意义(P>0.05). 结论脑缺血促使Trk受体表达增加与激活.β-NGF可能通过增强Trk磷酸化及调节Akt磷酸化发挥脑缺血保护作用.     

Activation of Trk neurotrophin receptors by glucocorticoids provides a neuroprotective effect

Glucocorticoids (GCs) display both protective and destructive effects in the nervous system. In excess, GCs produce neuronal damage after stress or brain injury; however, the neuroprotective effects of adrenal steroids also have been reported. The mechanisms that account for the positive actions are not well understood. Here we report that GCs can selectively activate Trk receptor tyrosine kinases after in vivo administration in the brain and in cultures of hippocampal and cortical neurons. Trk receptors are normally activated by neurotrophins, such as NGF and brain-derived neurotrophic factor, but the activation of Trk receptors by GCs does not depend on increased production of neurotrophins. Other tyrosine kinase receptors, such as EGF and FGF receptors, were not activated by GCs. The ability of GCs to increase Trk receptor activity resulted in the neuroprotection of neurons deprived of trophic support and could be modulated by steroid-converting enzymes. Pharmacological and shRNA experiments indicate that Trk receptor activation by GCs depends on a genomic action of the GC receptor. The ability of GCs to promote Trk receptor activity represents a molecular mechanism that integrates the actions of GCs and neurotrophins.     

Expression of trk in MAH cells lacking the p75 low-affinity nerve growth factor receptor is sufficient to permit nerve growth factor-induced differentiation to postmitotic neurons.

We have transfected MAH cells, an immortalized sympathoadrenal progenitor cell line, with a plasmid encoding the 140-kDa Trk protein, a nerve growth factor (NGF) receptor with protein-tyrosine kinase activity. NGF promotes neurite outgrowth and proliferation from such cells, indicating that Trk is sufficient to mediate such responses in the absence of significant levels of the endogenous 75-kDa low-affinity NGF receptor (p75). These initial NGF responses are indistinguishable from those evoked by basic fibroblast growth factor (bFGF). However, NGF is sufficient to promote terminal differentiation of a approximately 8% of trk-transfected MAH cells to postmitotic, NGF-dependent neurons, whereas all cells eventually die in medium with bFGF. Other environmental signals (such as depolarization or ciliary neurotrophic factor) can cooperate with NGF to enhance production of postmitotic NGF-dependent neurons in trk-transfected MAH cells. The terminal differentiation of sympathetic neurons thus involves sequential and cooperative actions of different growth and neurotrophic factors, as well as cell-intrinsic changes in the response to these factors.     

Activation of Trk neurotrophin receptors in the absence of neurotrophins

Neurotrophins regulate neuronal cell survival and synaptic plasticity through activation of Trk receptor tyrosine kinases. Binding of neurotrophins to Trk receptors results in receptor autophosphorylation and downstream phosphorylation cascades. Here, we describe an approach to use small molecule agonists to transactivate Trk neurotrophin receptors. Activation of TrkA receptors in PC12 cells and TrkB in hippocampal neurons was observed after treatment with adenosine, a neuromodulator that acts through G protein-coupled receptors. These effects were reproduced by using the adenosine agonist CGS 21680 and were counteracted with the antagonist ZM 241385, indicating that this transactivation event by adenosine involves adenosine 2A receptors. The increase in Trk activity could be inhibited by the use of the Src family-specific inhibitor, PP1, or K252a, an inhibitor of Trk receptors. In contrast to other G protein-coupled receptor transactivation events, adenosine used Trk receptor signaling with a longer time course. Moreover, adenosine activated phosphatidylinositol 3-kinase/Akt through a Trk-dependent mechanism that resulted in increased cell survival after nerve growth factor or brain-derived neurotrophic factor withdrawal. Therefore, adenosine acting through the A(2A) receptors exerts a trophic effect through the engagement of Trk receptors. These results provide an explanation for neuroprotective actions of adenosine through a unique signaling mechanism and raise the possibility that small molecules may be used to elicit neurotrophic effects for the treatment of neurodegenerative diseases.     

Coexpression of neurotrophins and their receptors in neurons of the central nervous system.

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are neuronal survival molecules which utilize the Trk family of tyrosine kinase receptors. Using double-label in situ hybridization, we demonstrate that mRNAs for BDNF and its high-affinity receptor TrkB are coexpressed in hippocampal and cortical neurons. Also, a large number of neurons in these areas coexpress NGF and BDNF mRNAs. Epileptic seizures lead to increased levels of both BDNF/TrkB and NGF/BDNF mRNAs in double-labeled cells. Our results show that individual neurons of the central nervous system can coexpress neurotrophins and their receptors and produce two neurotrophic factors. These factors could support neuronal survival after brain insults, not only via retrograde transport but also through autocrine mechanisms.     

Neurotrophins induce release of neurotrophins by the regulated secretory pathway

Recent studies have established that neurotrophin synthesis and secretion are regulated by activity and that these factors are involved in activity-dependent processes in the nervous system. Neurotrophins also are known to induce increases in intracellular calcium, a trigger for regulated secretion. This finding raises the possibility that neurotrophins themselves may stimulate regulated secretion of neurotrophins. To address this question, we studied the release of neurotrophins from transfected PC12 cells, a widely used model for neuronal secretion and neurotrophin signal transduction. We found that neurotrophins induced the regulated secretion of brain-derived neurotrophic factor, neurotrophin-3 (NT-3), and neurotrophin-4/5. The effect of brain-derived neurotrophic factor on release of NT-3 could be abolished by REX, a p75 blocking antibody, but not by K252a, an inhibitor of neurotrophin tyrosine kinase receptor (Trk) signaling. The nerve growth factor effect on release of NT-3 could be blocked only by simultaneous application of REX and K252a, suggesting that they are mediated by TrkA as well as p75. Our data show that neurotrophins are able to induce the regulated secretion of neurotrophins and suggest a signal-transducing role for both TrkA and p75 in this process. The neurotrophin-induced release of neurotrophins may be relevant for activity-dependent processes such as synaptic plasticity and memory formation.     

Dror, a potential neurotrophic receptor gene, encodes a Drosophila homolog of the vertebrate Ror family of Trk-related receptor tyrosine kinases.

We have identified a Drosophila gene, Dror, which encodes a putative receptor tyrosine kinase (RTK) and maps to cytological location 31B/C on the second chromosome. In embryos, this gene is expressed specifically in the developing nervous system. The Dror protein appears to be a homolog of two human RTKs, Ror1 and Ror2. Dror and Ror1 proteins share 36% amino acid identity in their extracellular domains and 61% identity in their catalytic tyrosine kinase (TK) domains. Ror1 and Ror2 were originally identified on the basis of the similarity of their TK domains to the TK domains of members of the Trk family of neurotrophin receptors. The Dror protein shows even greater similarity to the Trk proteins within this region than do the human Ror proteins. In light of its similarity to trk and its neural-specific expression pattern, we suggest that Dror may encode a neurotrophic receptor that functions during early stages of neural development in Drosophila.     

Ganglioside GM1 binds to the Trk protein and regulates receptor function.

Several lines of evidence have suggested that ganglioside GM1 stimulates neuronal sprouting and enhances the action of nerve growth factor (NGF), but its precise mechanism is yet to be elucidated. We report here that GM1 directly and tightly associates with Trk, the high-affinity tyrosine kinase-type receptor for NGF, and strongly enhances neurite outgrowth and neurofilament expression in rat PC12 cells elicited by a low dose of NGF that alone is insufficient to induce neuronal differentiation. The potentiation of NGF activity by GM1 appears to involve tyrosine-autophosphorylation of Trk, which contains intrinsic tyrosine kinase activity that has been localized to the cytoplasmic domain. In the presence of GM1 in culture medium, there is a > 3-fold increase in NGF-induced autophosphorylation of Trk as compared with NGF alone. We also found that GM1 could directly enhance NGF-activated autophosphorylation of immunoprecipitated Trk in vitro. Monosialoganglioside GM1, but not polysialogangliosides, is tightly associated with immunoprecipitated Trk. Furthermore, such tight association of GM1 with Trk appears to be specific, since a similar association was not observed with other growth factor receptors, such as low-affinity NGF receptor (p75NGR) and epidermal growth factor receptor (EGFR). Thus, these results strongly suggest that GM1 functions as a specific endogenous activator of NGF receptor function, and these enhanced effects appear to be due, at least in part, to tight association of GM1 with Trk.