Xc~-转运体和金属蛋白酶参与小脑颗粒神经元同型半胱氨酸引起ERK_(1/2)的磷酸化
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摘要
前言
细胞外信号调节激酶1和2 (ERK1/2)在苏氨酸／丝氨酸残基上发生磷酸化形成活化形式的ERK1/2 (p-ERK1/2)。该磷酸化及其下游的信号转导通路在神经元发育过程中具有重要意义。在成熟脑内,ERK1/2的磷酸化与记忆形成和突触可塑性密切相关。
高同型半胱氨酸血症与血管疾病,认知功能障碍,神经系统病变等有关,目前正在引起人们越来越多的关注。正常人同型半胱氨酸血浆浓度为10μM以下,随着年龄的增长有轻度升高的现象,同型半胱氨酸是必需氨基酸蛋氨酸的代谢产物,又可在蛋氨酸合成酶的作用下,重新甲基化为蛋氨酸,此过程需叶酸或维生素B12的参与。
在体内外试验中,暴露在不同浓度的同型半胱氨酸可引起细胞死亡。而同型半胱氨酸的毒性机制可能是刺激NMDA型谷氨酸受体和亲代谢型谷氨酸受体引起。另外,Robert发现在海马切片,100μM同型半胱氨酸引起的ERK1/2磷酸化可被NMDA、非NMDA和代谢型谷氨酸受体拮抗剂所抑制,表明谷氨酸释放参与此过程。
本试验中,微摩尔浓度的同型半胱氨酸在原代培养的小脑颗粒神经元通过上皮生长因子受体(EGFR)间接激活途径引起ERK1／2磷酸化。在EGFR间接激活中,Gq或Gi／o蛋白耦联受体激活或细胞内游离钙离子浓度升高,均可导致金属蛋白酶催化的EGFR配体释放,EGFR在脑内广泛存在。但在无必需氨基酸的盐溶液中孵育时,只有毫摩尔量的同型半胱氨酸才能引起ERK1／2磷酸化,且该磷酸化过程不依赖于间接激活。微摩尔量的同型半胱氨酸引起ERK1／2磷酸化需要谷氨酸前体谷氨酰胺存在。这些研究表明,微摩尔浓度同型半胱氨酸产生效应过程中可能存在Xc-转运体参与。同型半胱氨酸通过Xc-转运体与胱氨酸／谷氨酸交换,引起局部同型半胱氨酸浓度增高。
谷氨酸／胱氨酸转运体(glutamate/cystine transpoter)又称为Xc-系统,在Xc-系统作用下,细胞释放1分子的谷氨酸,并摄取1分子胱氨酸入胞,两者形成耦联转运。胱氨酸在胞内迅速被还原成半胱氨酸,一部分参与胞内重要自由基清除剂谷胱甘肽的合成,另一部分则出胞氧化成胱氨酸,重新参与Xc-系统循环。
金属蛋白酶对调节细胞微环境起重要作用,通过参与细胞外基质降解而影响细胞迁移、分化、增殖和存活。目前关于金属蛋白酶在脑内的表达是研究的热点。本课题组曾报道,在星形胶质细胞,金属蛋白酶参与EGFR间接激活途径,而与EGFR间接激活有关的金属蛋白酶为基质金属蛋白酶(MMP),含去整合素域和金属蛋白酶域的蛋白酶(ADAM)。本篇文章主要研究Xc-转运体和金属蛋白酶在小脑颗粒神经元同型半胱氨酸引起ERK1／2磷酸化中的作用。即(1)阐明同型半胱氨酸引起小脑颗粒神经元上皮生长因子受体间接激活的信号转导途径。(2)研究System Xc系统是否参与同型半胱氨酸引起小脑颗粒神经元ERK1／2磷酸化的过程。(3)神经元和星形胶质细胞上存在的MMP和ADAM类型。(4)参与神经细胞上皮生长因子受体间接激活信号转导途径的金属蛋白酶类型。
方法
采用原代培养的小脑颗粒神经元。将细胞在37℃无血清相关培养液中孵育20分钟,含有不同浓度的同型半胱氨酸以及相关特异性抑制剂。应用冰PBS洗涤细胞,加入裂解液,终止反应,收集细胞。进行凝胶电泳,免疫印迹分析。使用SPSS12.0软件进行统计学分析,多组资料用one-way ANOVA方法进行比较,P<0.05表示差异具有统计学意义。
结果
1、同型半胱氨酸诱导的ERK1／2磷酸化呈时间和浓度依赖性。
将细胞在培养液(含必需氨基酸、2 mM谷氨酰胺、200 gM胱氨酸)中孵育20分钟。在同型半胱氨酸浓度为100μM及大于100μM时,磷酸化水平开始升高。曲线表明同型半胱氨酸引起ERK1／2磷酸化是浓度依赖性的,而且100μM和1 mM同型半胱氨酸作用在细胞10分钟后,p-ERK1／2开始升高,两者均是在20分钟时升高最为显著且具有统计学意义,在40分钟时下降。
2、EGFR(酪氨酸激酶受体)和锌依赖的金属蛋白酶参与同型半胱氨酸引起的ERK11／2磷酸化。
AG1478为上皮生长因子受体特异性抑制剂,GM6001为金属蛋白酶抑制剂。二者均可抑制同型半胱氨酸20分钟时引起的ERK1／2磷酸化增加,说明此过程为EGFR间接激活途径,并且EGFR间接激活是依赖于金属蛋白酶裂解EGF受体的配体脱落进而激活EGFR。
3、NMDA和非NMDA受体参与同型半胱氨酸诱导的ERK1／2磷酸化。
MK801为NMDA受体拮抗剂,CNQX为非NMDA受体拮抗剂,二者均可完全阻断100μM同型半胱氨酸诱导的ERK1／2磷酸化,而对1 mM同型半胱氨酸引起的ERK1／2磷酸化抑制程度不完全,提示1 mM同型半胱氨酸引起ERK1／2磷酸化过程中可能存在其他信号传导途径。
4、在不含必需氨基酸的PBS中,代谢型谷氨酸受体参与毫摩尔浓度同型半胱氨酸引起的ERK1／2磷酸化。
上述实验均在含必需氨基酸、2 mM谷氨酰胺和200μM胱氨酸条件下得到。但在不含必需氨基酸的PBS中,1 mM同型半胱氨酸并不引起ERK1／2磷酸化,2 mM同型半胱氨酸开始引起ERK1／2磷酸化,并且有统计学意义,在10mM-15mM时达到最大。AG1478、GM6001、MK801和CNQX均不能抑制ERK1／2的磷酸化,但是,10 mM同型半胱氨酸诱导的ERK1／2磷酸化可以被mGluR1抑制剂LY367385和mGluR5抑制剂MPEP所抑制。
5、同型半胱氨酸诱导的ERK1／2磷酸化可被DIDS和SPAP抑制。
我们用Xc-转运体抑制剂100μM DIDS、300μM SPAP来检测Xc-转运体是否参与同型半胱氨酸引起的ERK1／2磷酸化。结果两种抑制剂均可阻断ERK1／2磷酸化,表明ERK磷酸化依赖于Xc-转运体。
6、MMP和ADAM在小脑颗粒神经元和星形胶质细胞上的表达。
我们用逆转录聚合酶链反应检测MMP和ADAM在小脑颗粒神经元和星形胶质细胞的表达,发现存在15种表达。其中,与脑组织相比,在星形胶质细胞,MMP15、MMP24、MMP25表达减少,而MMP9在神经元表达减少。
讨论
1、微摩尔和毫摩尔浓度同型半胱氨酸作用的比较
NMDA和非NMDA受体拮抗剂均可完全阻断100μM同型半胱氨酸引起的ERK1／2磷酸化,表明NMDA和非NMDA受体相继激活,上述反应要求介质中谷氨酰胺存在。而当无谷氨酰胺存在时需要十倍浓度的同型半胱氨酸才能引起反应。在此条件下,ERK1／2磷酸化不依赖于间接激活,离子型谷氨酸受体拮抗剂不能抑制ERK1／2磷酸化,但是代谢型谷氨酸受体mGluR1和mGluR5抑制剂确能阻断此反应。
2、谷氨酰胺和Xc-转运体的作用
微摩尔浓度同型半胱氨酸诱导ERK1／2磷酸化需要谷氨酸前体谷氨酰胺的存在,表明Xc-转运体可能参与此过程,用Xc-转运体抑制剂]DIDS和SPAP可抑制反应证实了这一点。Xc-转运体在生理上是细胞内的谷氨酸和细胞外的胱氨酸转运体。使君子氨酸既是Xc-转运体的底物,又是非NMDA受体激动剂。而且,使君子氨酸可以“自我敏感化”。因为同型半胱氨酸既是谷氨酸受体激动剂而且可与Xc-转运体作用,因此我们猜测同型半胱氨酸也有类似的“自我致敏”作用,而且上述实验结果也与此相符。
在小脑颗粒神经元内谷氨酰胺酶作用下,谷氨酰胺可代谢为谷氨酸,细胞外液中含有一定浓度的谷氨酰胺时可以激活Xc-转运体,使细胞外谷氨酸与细胞内累积得同型半胱氨酸交换。
3、同型半胱氨酸的神经毒性作用
体内同型半胱氨酸的神经毒性作用很可能是因为微摩尔浓度的同型半胱氨酸激活离子型受体所致。目前研究揭示胱氨酸／谷氨酸交换体介导的“自我致敏”作用在临床相关浓度同型半胱氨酸的神经毒性中起重要作用。提示我们转运体抑制剂可能对高同型半胱氨酸血症有神经保护作用。Ferrer等人研究证明ERK1／2磷酸化可对抗兴奋性中毒而起神经保护作用。
4、金属蛋白酶在星形胶质细胞和神经元的表达及其在EGFR间接激活中的作用
有人利用核糖核酸酶保护测定发现在成年小鼠脑内存在低水平的MMP2、MMP9、MMP11、MMP12、MMP14表达,但我们却发现MMP2和MMP9在小鼠脑内表达水平比较高。ADAMs已被证明在多种动物脑内存在,而Iivari Karkkainen等人证实其在小鼠脑内的存在。另外,我们发现在小鼠脑内存在15种Mps表达,并且与脑组织相比,在星形胶质细胞,MMP15、MMP24、MMP25表达减少,而MMP9在神经元表达减少。组织金属蛋白酶抑制剂1(TIMP-1)对MT-MMPs几乎无抑制作用,而TIMP-2则可以抑制全部MMP。因此,我们可以应用TIMP-1和TIMP-2来检测MT-MMP是否参与蛋白酶裂解。许多研究表明,ADAM家族成员参与膜锚定蛋白外功能区脱落进而引起生理功能的改变。但有趣的是,我们在实验中发现ADAM 17参与KCl引起星形胶质细胞ERK1／2磷酸化,但KCl引起小脑颗粒神经元ERK1／2磷酸化却不需要ADAM17参与。
结论
1、同型半胱氨酸通过EGFR间接激活及Xc-转运体的自我致敏作用在小脑颗粒神经元引起ERK1／2的磷酸化。
2、15种金属蛋白酶在星形胶质细胞和小脑颗粒神经元均有表达。
Introduction
Phosphorylation of extracellular-signal regulated kinase (ERK) 1 and 2 (ERK1/2) generates extracellular-signal regulated kinase 1 and extracellular-signal regulated kinase 2 phosphorylated at serine/threonine residues (p-ERKi/2), the active form of ERK1/2.This activation and ensuing downstream signaling is important for many neuronal functions during development and in the adult brain, where it plays a major role in plasticity and thus in memory formation.
Hyperhomocysteinemia is associated with vascular disease and cognitive and neurologic dysfunction. Normally homocysteine is present at plasma concentrations of～10μM, with a slight increase during aging. Homocysteine is formed from the essential amino acid methionine and can be re-converted to methionine by the cobalamine-(vitamin B12) and folate-dependent homocysteine methyltransferase.
Exposure to homocysteine at micromolar to millimolar concentrations induces cell death by several different routes in neurons in vivo and in vitro. Robert et al. showed in hippocampal slices that 100μM homocysteine caused phosphorylation of extracellularregulated kinases 1 and 2 (ERK1/2) that was inhibited not only by NMDA or metabotropic glutamate receptor antagonists but also by a non-NMDA receptor antagonist in 2005, and suggested that the response was secondary to glutamate release.
In this study micromolar homocysteine-mediated ERK1/2 phosphorylation was replicated in cultured cerebellar granule neurons incubated in tissue culture medium. It involved transactivation, a process where activation of Gi/o or Gq protein-coupled receptors or increase in [Ca2+]i leads to metalloproteinase-catalyzed shedding of an agonist at the epidermal growth factor (EGF) receptor, stimulating EGF receptors, which are widespread in brain. During incubation in amino-acid free saline medium millimolar concentrations of homocysteine were required to obtain ERK1/2 phosphorylation, which was independent of transactivation. Glutamine, an obligatory glutamate precursor, restored the potent response. These findings suggest that this system Xc- may be involved in the micromolar effect of homocysteine.
Glutamate/cystine transpoter, designated as system Xc-, transports an anionic form of cystine in exchange for glutamate. The cells expressing system Xc- take up cystine in the medium and reduce it to cysteine, which is in turn used for the synthesis of glutathione and proteins. A part of cysteine is released back into the medium via neutral amino acid transport systems; then cysteine is rapidly oxidized to cystine by oxygen in the medium.
Metalloproteinases (MPs) play key roles in the responses of cells to their microenvironment. By effecting proteolytic degradation or activation of cell surface and extracellular matrix (ECM) proteins they can modulate both cell-cell and cell-ECM interactions, which influence cell differentiation, migration, proliferation and survival. Our previous work suggested that metalloproteinases played an important role in transactivation of epidermal growth factor receptors (EGFR) following activation of G-protein coupled receptors in cultured astrocytes. The forms of metalloproteinases have been implicated in transactivation of EGFR including the matrix metalloproteinases (MMPs), the adamalysin-like proteinases with both metalloproteinase and disintegrin-like domains (ADAMs). In the present study we have studied the mechanism of ERK1/2 phosphorylation during homocysteine-induced, metalloproteinases-mediated using 7-8-day-old primary cultures of cerebellar granule neurons. (1) Homocysteine-induced ERK1/2 phosphorylation is transactivation of epidermal growth factor receptors (EGFRs). (2) Homocysteine-induced ERK1/2 phosphorylation is mediated by system Xc-.(3) Expression of metalloproteinases in cultured astrocytes and neurons and the role of it in the EGFR transactivation.
Methods
The primary cerebellar granule neuron culture were the pre-incubate in the corresponding medium without serum at 37℃at different concentration of the homocysteine in the absence or presence of specific inhibitors. The reaction was stopped by washing with ice-cold phosphate-buffered saline (PBS) containing 7.5 mM glucose, and the cells were scraped off the dishes and harvested in 0.5 ml of ice-cold buffer for Western-Blot. The results are analysised with one-way ANOVA by SPSS12.0 software. P＜0.05 indicate the statically significant difference.
Results
1、Homocysteine-induced ERK1/2 phosphorylation is concentration-and time-dependent.
Exposure of cerebellar granule neurons to homocysteine for 20 min during incubation in tissue culture medium (containing essential amino acids,2 mM glutamine and 200μM cystine) caused an increase of p-ERK1/2at homocysteine concentrations at or above 100μM. The course of the effects as a function of the homocysteine concentration suggests a dose-dependent effect. Regardless whether the homocysteine concentration was 100μM or 1 mM maximum response occurred after 20 min, with a beginning increase at 10 min, and followed by a decline towards control values at 40 mm.
2、EGF receptor-tyrosine kinase and Zn2+-dependent metalloproteina-se are involved in potent homocysteine-induced ERK1/2 phosphorylation.
In the presence of 1μM AG1478, a specific EGF receptor-activated tyrosine kinase inhibitor, or of 10μM GM6001, an inhibitor of metalloproteinases, ERK1/2 phosphorylation after incubation with homocysteine for 20 min was inhibited, indicating EGF transactivation, which depends on metalloproteinase-catalyzed release of an agonist at the EGF receptor.
3、NMDA and non-NMDA receptors are involved in potent homocysteine-induced ERK1/2 phosphorylation.
MK801, an antagonist of NMDA receptors, and CNQX, an antagonist of non-NMDA ionotropic glutamate receptors individually abolished the stimulation by 100μM homocysteine. Again, the effect of the two inhibitors seemed less complete at 1 mM of homocysteine, suggesting that mechanisms independent of ionotropic glutamate receptors and of transactivation may also contribute to ERK1/2 phosphorylation in the presence of 1 mM homocysteine.
4、Metabotropic glutamate receptors are involved in ERK1/2 phosphorylation by millimolar homocysteine concentrations in amino-acid free PBS.
All experiments shown up until now were carried out in tissue culture medium containing essential amino acids, glutamine (2 mM), and cystine (200μM). However, when a dose-response study was carried out in PBS without any amino acids, one mM homocysteine had no significant effect on ERK1/2 phosphorylation, two mM homocysteine had a statistically significant effect and a maximum stimulation required homocysteine concentrations of at least 10-15 mM. Moreover, AG1478, GM6001, MK801 and CNQX can not inhibited ERK1/2 phosphorylation. However, ERK phosphorylation induced by 10 mM homocysteine was substantially reduced by either the mGluRl inhibitor LY367385 or the mGluR5 inhibitor MPEP.
5、Potent homocysteine-induced ERK1/2 phosphorylation is inhibited by DIDS and SPAP.
To substantiate the notion that system Xc- is essential for the potent response to homocysteine its potential inhibition was tested in the presence of the system Xc-inhibitors,100μM DIDS, or 300μM SPAP. Either inhibitor abolished ERK1/2 phosphorylation, establishing the dependence of potent ERK phosphorylation on system Xc-.
6、Compared with brain tissue, astrocytes expressed less, MMP15, MMP24 and MMP25 and neurons had less MMP9.
We examined the mRNA expression of these MMPs and ADAMs in primary cultures of mouse astrocytes and cerebellar granule neurons by reverse transcriptase PCR (RT-PCR). We found that all of 15 MMPs and ADAMs expressed in brain in vivo were also expressed in cultured astrocytes and neurons. As compared with brain tissue, astrocytes expressed less MMP15, MMP24 and MMP25 and neurons had less MMP9.
Discussion
1、Micromolar versus millimolar homocysteine effects
The complete inhibition by either antagonist, at least at 100μM homocysteine, suggests a sequential stimulation of non-NMDA and NMDA receptors, the response required the presence of glutamine in the medium. In the absence of glutamine 10-fold higher concentrations of homocysteine were required. Under these conditions ERK1/2 phosphorylation was transactivation-independent, and antagonists of ionotropic receptors had no inhibitory effect, whereas inhibitors of metabotropic glutamate receptors of group I (mGluRl and mGluR5) greatly reduced the response.
2、Dependence on glutamine and the role of system Xc-
The dependence of micromolar homocysteine-induced potent ERK1/2 phosphorylation on the presence of glutamine, as a precursor of glutamate, suggested the involvement of system Xc-, a conclusion, which was supported by the inhibitory effect of both DIDS and SPAP. System Xc- functions physiologically as an exchanger between intracellular glutamate and extracellular cystine. Quisqualate is both a system Xc- substrate and an agonist at non-NMDA receptors, moreover, it can "self-sensitize". Since homocysteine is both a glutamate receptor agonist and interacts with system Xc-, a similar"self-sensitization"can be expected and can explain the present results.
The dependence on glutamine, which is gradually metabolized to glutamate by a high glutaminase activity in cerebellar granule neurons, suggests that release of intracellularly accumulated homocysteine by system Xc-, is triggered by extracellular availability of glutamate after the exposure to extracellular glutamine.
3、Neurotoxicity of homocysteine
Activation of ionotropic receptors by micromolar concentrations of homocysteine are likely to contribute to neurotoxic effects of homocysteine in vivo. The present study, pointing out the crucial role of cystine-glutamate exchanger-mediated "self-sensitization"for neuronal effects of clinically relevant homocysteine concentrations, calls for additional studies whether or not pharmacological inhibition of this system. In addition, Ferrer et al. found a neuroprotective effect of ERK1/2 phosphorylation against excitotoxicity.
4、Expression of metalloproteinases in cultured astrocytes and neurons and the role of it in the EGFR transactivation
Someones used an RNase protection assay to show that among MMP-2,-9,-11,-12 and-14 were expressed, and mostly at rather low levels, in the mouse brain. But we found in the mouse brain MMP2 and MMP9 mRNA are particularly abundant. The presence of some ADAM mRNAs in the brain of a variety of animal species, demonstrated elsewhere, was confirmed for the mouse brain by Iivari Karkkainen. We found that all of 15 Mps expressed in brain in vivo were also expressed in cultured astrocytes and neurons. As compared with brain tissue, astrocytes expressed less MMP15, MMP24 and MMP25 and neurons had less MMP9. Tissue inhibitors of metalloproteinases-2(TIMP-2) can inhibit active forms of all MMPs studied to date, although TIMP-1 is a poor inhibitor of a number of the MT-MMPs. To detect whether the MT-MMP is essential for the potent shedding, we can use TIMP-1 and TIMP-2. A great deal of data has been collected regarding ectodomain shedding is predominantly mediated by ADAM. Intrerestly, we found ERK1/2 phosphorylation induced by KCl requires ADAM17 function in astrocytes, but does not require ADAM17 function in cerebellar granule neurons.
Conclusion
1、Potent homocysteine-induced ERK1/2 phosphorylation in cultured neurons via EGFR transactivation and depends on system Xc-self-sensitization.
2、We found 15 MMPs and ADAMs expressed in brain in vivo were also expressed in cultured astrocytes and neurons.
细胞外信号调节激酶1和2 (ERK1/2)在苏氨酸／丝氨酸残基上发生磷酸化形成活化形式的ERK1/2 (p-ERK1/2)。该磷酸化及其下游的信号转导通路在神经元发育过程中具有重要意义。在成熟脑内,ERK1/2的磷酸化与记忆形成和突触可塑性密切相关。
高同型半胱氨酸血症与血管疾病,认知功能障碍,神经系统病变等有关,目前正在引起人们越来越多的关注。正常人同型半胱氨酸血浆浓度为10μM以下,随着年龄的增长有轻度升高的现象,同型半胱氨酸是必需氨基酸蛋氨酸的代谢产物,又可在蛋氨酸合成酶的作用下,重新甲基化为蛋氨酸,此过程需叶酸或维生素B12的参与。
在体内外试验中,暴露在不同浓度的同型半胱氨酸可引起细胞死亡。而同型半胱氨酸的毒性机制可能是刺激NMDA型谷氨酸受体和亲代谢型谷氨酸受体引起。另外,Robert发现在海马切片,100μM同型半胱氨酸引起的ERK1/2磷酸化可被NMDA、非NMDA和代谢型谷氨酸受体拮抗剂所抑制,表明谷氨酸释放参与此过程。
本试验中,微摩尔浓度的同型半胱氨酸在原代培养的小脑颗粒神经元通过上皮生长因子受体(EGFR)间接激活途径引起ERK1／2磷酸化。在EGFR间接激活中,Gq或Gi／o蛋白耦联受体激活或细胞内游离钙离子浓度升高,均可导致金属蛋白酶催化的EGFR配体释放,EGFR在脑内广泛存在。但在无必需氨基酸的盐溶液中孵育时,只有毫摩尔量的同型半胱氨酸才能引起ERK1／2磷酸化,且该磷酸化过程不依赖于间接激活。微摩尔量的同型半胱氨酸引起ERK1／2磷酸化需要谷氨酸前体谷氨酰胺存在。这些研究表明,微摩尔浓度同型半胱氨酸产生效应过程中可能存在Xc-转运体参与。同型半胱氨酸通过Xc-转运体与胱氨酸／谷氨酸交换,引起局部同型半胱氨酸浓度增高。
谷氨酸／胱氨酸转运体(glutamate/cystine transpoter)又称为Xc-系统,在Xc-系统作用下,细胞释放1分子的谷氨酸,并摄取1分子胱氨酸入胞,两者形成耦联转运。胱氨酸在胞内迅速被还原成半胱氨酸,一部分参与胞内重要自由基清除剂谷胱甘肽的合成,另一部分则出胞氧化成胱氨酸,重新参与Xc-系统循环。
金属蛋白酶对调节细胞微环境起重要作用,通过参与细胞外基质降解而影响细胞迁移、分化、增殖和存活。目前关于金属蛋白酶在脑内的表达是研究的热点。本课题组曾报道,在星形胶质细胞,金属蛋白酶参与EGFR间接激活途径,而与EGFR间接激活有关的金属蛋白酶为基质金属蛋白酶(MMP),含去整合素域和金属蛋白酶域的蛋白酶(ADAM)。本篇文章主要研究Xc-转运体和金属蛋白酶在小脑颗粒神经元同型半胱氨酸引起ERK1／2磷酸化中的作用。即(1)阐明同型半胱氨酸引起小脑颗粒神经元上皮生长因子受体间接激活的信号转导途径。(2)研究System Xc系统是否参与同型半胱氨酸引起小脑颗粒神经元ERK1／2磷酸化的过程。(3)神经元和星形胶质细胞上存在的MMP和ADAM类型。(4)参与神经细胞上皮生长因子受体间接激活信号转导途径的金属蛋白酶类型。
方法
采用原代培养的小脑颗粒神经元。将细胞在37℃无血清相关培养液中孵育20分钟,含有不同浓度的同型半胱氨酸以及相关特异性抑制剂。应用冰PBS洗涤细胞,加入裂解液,终止反应,收集细胞。进行凝胶电泳,免疫印迹分析。使用SPSS12.0软件进行统计学分析,多组资料用one-way ANOVA方法进行比较,P<0.05表示差异具有统计学意义。
结果
1、同型半胱氨酸诱导的ERK1／2磷酸化呈时间和浓度依赖性。
将细胞在培养液(含必需氨基酸、2 mM谷氨酰胺、200 gM胱氨酸)中孵育20分钟。在同型半胱氨酸浓度为100μM及大于100μM时,磷酸化水平开始升高。曲线表明同型半胱氨酸引起ERK1／2磷酸化是浓度依赖性的,而且100μM和1 mM同型半胱氨酸作用在细胞10分钟后,p-ERK1／2开始升高,两者均是在20分钟时升高最为显著且具有统计学意义,在40分钟时下降。
2、EGFR(酪氨酸激酶受体)和锌依赖的金属蛋白酶参与同型半胱氨酸引起的ERK11／2磷酸化。
AG1478为上皮生长因子受体特异性抑制剂,GM6001为金属蛋白酶抑制剂。二者均可抑制同型半胱氨酸20分钟时引起的ERK1／2磷酸化增加,说明此过程为EGFR间接激活途径,并且EGFR间接激活是依赖于金属蛋白酶裂解EGF受体的配体脱落进而激活EGFR。
3、NMDA和非NMDA受体参与同型半胱氨酸诱导的ERK1／2磷酸化。
MK801为NMDA受体拮抗剂,CNQX为非NMDA受体拮抗剂,二者均可完全阻断100μM同型半胱氨酸诱导的ERK1／2磷酸化,而对1 mM同型半胱氨酸引起的ERK1／2磷酸化抑制程度不完全,提示1 mM同型半胱氨酸引起ERK1／2磷酸化过程中可能存在其他信号传导途径。
4、在不含必需氨基酸的PBS中,代谢型谷氨酸受体参与毫摩尔浓度同型半胱氨酸引起的ERK1／2磷酸化。
上述实验均在含必需氨基酸、2 mM谷氨酰胺和200μM胱氨酸条件下得到。但在不含必需氨基酸的PBS中,1 mM同型半胱氨酸并不引起ERK1／2磷酸化,2 mM同型半胱氨酸开始引起ERK1／2磷酸化,并且有统计学意义,在10mM-15mM时达到最大。AG1478、GM6001、MK801和CNQX均不能抑制ERK1／2的磷酸化,但是,10 mM同型半胱氨酸诱导的ERK1／2磷酸化可以被mGluR1抑制剂LY367385和mGluR5抑制剂MPEP所抑制。
5、同型半胱氨酸诱导的ERK1／2磷酸化可被DIDS和SPAP抑制。
我们用Xc-转运体抑制剂100μM DIDS、300μM SPAP来检测Xc-转运体是否参与同型半胱氨酸引起的ERK1／2磷酸化。结果两种抑制剂均可阻断ERK1／2磷酸化,表明ERK磷酸化依赖于Xc-转运体。
6、MMP和ADAM在小脑颗粒神经元和星形胶质细胞上的表达。
我们用逆转录聚合酶链反应检测MMP和ADAM在小脑颗粒神经元和星形胶质细胞的表达,发现存在15种表达。其中,与脑组织相比,在星形胶质细胞,MMP15、MMP24、MMP25表达减少,而MMP9在神经元表达减少。
讨论
1、微摩尔和毫摩尔浓度同型半胱氨酸作用的比较
NMDA和非NMDA受体拮抗剂均可完全阻断100μM同型半胱氨酸引起的ERK1／2磷酸化,表明NMDA和非NMDA受体相继激活,上述反应要求介质中谷氨酰胺存在。而当无谷氨酰胺存在时需要十倍浓度的同型半胱氨酸才能引起反应。在此条件下,ERK1／2磷酸化不依赖于间接激活,离子型谷氨酸受体拮抗剂不能抑制ERK1／2磷酸化,但是代谢型谷氨酸受体mGluR1和mGluR5抑制剂确能阻断此反应。
2、谷氨酰胺和Xc-转运体的作用
微摩尔浓度同型半胱氨酸诱导ERK1／2磷酸化需要谷氨酸前体谷氨酰胺的存在,表明Xc-转运体可能参与此过程,用Xc-转运体抑制剂]DIDS和SPAP可抑制反应证实了这一点。Xc-转运体在生理上是细胞内的谷氨酸和细胞外的胱氨酸转运体。使君子氨酸既是Xc-转运体的底物,又是非NMDA受体激动剂。而且,使君子氨酸可以“自我敏感化”。因为同型半胱氨酸既是谷氨酸受体激动剂而且可与Xc-转运体作用,因此我们猜测同型半胱氨酸也有类似的“自我致敏”作用,而且上述实验结果也与此相符。
在小脑颗粒神经元内谷氨酰胺酶作用下,谷氨酰胺可代谢为谷氨酸,细胞外液中含有一定浓度的谷氨酰胺时可以激活Xc-转运体,使细胞外谷氨酸与细胞内累积得同型半胱氨酸交换。
3、同型半胱氨酸的神经毒性作用
体内同型半胱氨酸的神经毒性作用很可能是因为微摩尔浓度的同型半胱氨酸激活离子型受体所致。目前研究揭示胱氨酸／谷氨酸交换体介导的“自我致敏”作用在临床相关浓度同型半胱氨酸的神经毒性中起重要作用。提示我们转运体抑制剂可能对高同型半胱氨酸血症有神经保护作用。Ferrer等人研究证明ERK1／2磷酸化可对抗兴奋性中毒而起神经保护作用。
4、金属蛋白酶在星形胶质细胞和神经元的表达及其在EGFR间接激活中的作用
有人利用核糖核酸酶保护测定发现在成年小鼠脑内存在低水平的MMP2、MMP9、MMP11、MMP12、MMP14表达,但我们却发现MMP2和MMP9在小鼠脑内表达水平比较高。ADAMs已被证明在多种动物脑内存在,而Iivari Karkkainen等人证实其在小鼠脑内的存在。另外,我们发现在小鼠脑内存在15种Mps表达,并且与脑组织相比,在星形胶质细胞,MMP15、MMP24、MMP25表达减少,而MMP9在神经元表达减少。组织金属蛋白酶抑制剂1(TIMP-1)对MT-MMPs几乎无抑制作用,而TIMP-2则可以抑制全部MMP。因此,我们可以应用TIMP-1和TIMP-2来检测MT-MMP是否参与蛋白酶裂解。许多研究表明,ADAM家族成员参与膜锚定蛋白外功能区脱落进而引起生理功能的改变。但有趣的是,我们在实验中发现ADAM 17参与KCl引起星形胶质细胞ERK1／2磷酸化,但KCl引起小脑颗粒神经元ERK1／2磷酸化却不需要ADAM17参与。
结论
1、同型半胱氨酸通过EGFR间接激活及Xc-转运体的自我致敏作用在小脑颗粒神经元引起ERK1／2的磷酸化。
2、15种金属蛋白酶在星形胶质细胞和小脑颗粒神经元均有表达。
Introduction
Phosphorylation of extracellular-signal regulated kinase (ERK) 1 and 2 (ERK1/2) generates extracellular-signal regulated kinase 1 and extracellular-signal regulated kinase 2 phosphorylated at serine/threonine residues (p-ERKi/2), the active form of ERK1/2.This activation and ensuing downstream signaling is important for many neuronal functions during development and in the adult brain, where it plays a major role in plasticity and thus in memory formation.
Hyperhomocysteinemia is associated with vascular disease and cognitive and neurologic dysfunction. Normally homocysteine is present at plasma concentrations of～10μM, with a slight increase during aging. Homocysteine is formed from the essential amino acid methionine and can be re-converted to methionine by the cobalamine-(vitamin B12) and folate-dependent homocysteine methyltransferase.
Exposure to homocysteine at micromolar to millimolar concentrations induces cell death by several different routes in neurons in vivo and in vitro. Robert et al. showed in hippocampal slices that 100μM homocysteine caused phosphorylation of extracellularregulated kinases 1 and 2 (ERK1/2) that was inhibited not only by NMDA or metabotropic glutamate receptor antagonists but also by a non-NMDA receptor antagonist in 2005, and suggested that the response was secondary to glutamate release.
In this study micromolar homocysteine-mediated ERK1/2 phosphorylation was replicated in cultured cerebellar granule neurons incubated in tissue culture medium. It involved transactivation, a process where activation of Gi/o or Gq protein-coupled receptors or increase in [Ca2+]i leads to metalloproteinase-catalyzed shedding of an agonist at the epidermal growth factor (EGF) receptor, stimulating EGF receptors, which are widespread in brain. During incubation in amino-acid free saline medium millimolar concentrations of homocysteine were required to obtain ERK1/2 phosphorylation, which was independent of transactivation. Glutamine, an obligatory glutamate precursor, restored the potent response. These findings suggest that this system Xc- may be involved in the micromolar effect of homocysteine.
Glutamate/cystine transpoter, designated as system Xc-, transports an anionic form of cystine in exchange for glutamate. The cells expressing system Xc- take up cystine in the medium and reduce it to cysteine, which is in turn used for the synthesis of glutathione and proteins. A part of cysteine is released back into the medium via neutral amino acid transport systems; then cysteine is rapidly oxidized to cystine by oxygen in the medium.
Metalloproteinases (MPs) play key roles in the responses of cells to their microenvironment. By effecting proteolytic degradation or activation of cell surface and extracellular matrix (ECM) proteins they can modulate both cell-cell and cell-ECM interactions, which influence cell differentiation, migration, proliferation and survival. Our previous work suggested that metalloproteinases played an important role in transactivation of epidermal growth factor receptors (EGFR) following activation of G-protein coupled receptors in cultured astrocytes. The forms of metalloproteinases have been implicated in transactivation of EGFR including the matrix metalloproteinases (MMPs), the adamalysin-like proteinases with both metalloproteinase and disintegrin-like domains (ADAMs). In the present study we have studied the mechanism of ERK1/2 phosphorylation during homocysteine-induced, metalloproteinases-mediated using 7-8-day-old primary cultures of cerebellar granule neurons. (1) Homocysteine-induced ERK1/2 phosphorylation is transactivation of epidermal growth factor receptors (EGFRs). (2) Homocysteine-induced ERK1/2 phosphorylation is mediated by system Xc-.(3) Expression of metalloproteinases in cultured astrocytes and neurons and the role of it in the EGFR transactivation.
Methods
The primary cerebellar granule neuron culture were the pre-incubate in the corresponding medium without serum at 37℃at different concentration of the homocysteine in the absence or presence of specific inhibitors. The reaction was stopped by washing with ice-cold phosphate-buffered saline (PBS) containing 7.5 mM glucose, and the cells were scraped off the dishes and harvested in 0.5 ml of ice-cold buffer for Western-Blot. The results are analysised with one-way ANOVA by SPSS12.0 software. P＜0.05 indicate the statically significant difference.
Results
1、Homocysteine-induced ERK1/2 phosphorylation is concentration-and time-dependent.
Exposure of cerebellar granule neurons to homocysteine for 20 min during incubation in tissue culture medium (containing essential amino acids,2 mM glutamine and 200μM cystine) caused an increase of p-ERK1/2at homocysteine concentrations at or above 100μM. The course of the effects as a function of the homocysteine concentration suggests a dose-dependent effect. Regardless whether the homocysteine concentration was 100μM or 1 mM maximum response occurred after 20 min, with a beginning increase at 10 min, and followed by a decline towards control values at 40 mm.
2、EGF receptor-tyrosine kinase and Zn2+-dependent metalloproteina-se are involved in potent homocysteine-induced ERK1/2 phosphorylation.
In the presence of 1μM AG1478, a specific EGF receptor-activated tyrosine kinase inhibitor, or of 10μM GM6001, an inhibitor of metalloproteinases, ERK1/2 phosphorylation after incubation with homocysteine for 20 min was inhibited, indicating EGF transactivation, which depends on metalloproteinase-catalyzed release of an agonist at the EGF receptor.
3、NMDA and non-NMDA receptors are involved in potent homocysteine-induced ERK1/2 phosphorylation.
MK801, an antagonist of NMDA receptors, and CNQX, an antagonist of non-NMDA ionotropic glutamate receptors individually abolished the stimulation by 100μM homocysteine. Again, the effect of the two inhibitors seemed less complete at 1 mM of homocysteine, suggesting that mechanisms independent of ionotropic glutamate receptors and of transactivation may also contribute to ERK1/2 phosphorylation in the presence of 1 mM homocysteine.
4、Metabotropic glutamate receptors are involved in ERK1/2 phosphorylation by millimolar homocysteine concentrations in amino-acid free PBS.
All experiments shown up until now were carried out in tissue culture medium containing essential amino acids, glutamine (2 mM), and cystine (200μM). However, when a dose-response study was carried out in PBS without any amino acids, one mM homocysteine had no significant effect on ERK1/2 phosphorylation, two mM homocysteine had a statistically significant effect and a maximum stimulation required homocysteine concentrations of at least 10-15 mM. Moreover, AG1478, GM6001, MK801 and CNQX can not inhibited ERK1/2 phosphorylation. However, ERK phosphorylation induced by 10 mM homocysteine was substantially reduced by either the mGluRl inhibitor LY367385 or the mGluR5 inhibitor MPEP.
5、Potent homocysteine-induced ERK1/2 phosphorylation is inhibited by DIDS and SPAP.
To substantiate the notion that system Xc- is essential for the potent response to homocysteine its potential inhibition was tested in the presence of the system Xc-inhibitors,100μM DIDS, or 300μM SPAP. Either inhibitor abolished ERK1/2 phosphorylation, establishing the dependence of potent ERK phosphorylation on system Xc-.
6、Compared with brain tissue, astrocytes expressed less, MMP15, MMP24 and MMP25 and neurons had less MMP9.
We examined the mRNA expression of these MMPs and ADAMs in primary cultures of mouse astrocytes and cerebellar granule neurons by reverse transcriptase PCR (RT-PCR). We found that all of 15 MMPs and ADAMs expressed in brain in vivo were also expressed in cultured astrocytes and neurons. As compared with brain tissue, astrocytes expressed less MMP15, MMP24 and MMP25 and neurons had less MMP9.
Discussion
1、Micromolar versus millimolar homocysteine effects
The complete inhibition by either antagonist, at least at 100μM homocysteine, suggests a sequential stimulation of non-NMDA and NMDA receptors, the response required the presence of glutamine in the medium. In the absence of glutamine 10-fold higher concentrations of homocysteine were required. Under these conditions ERK1/2 phosphorylation was transactivation-independent, and antagonists of ionotropic receptors had no inhibitory effect, whereas inhibitors of metabotropic glutamate receptors of group I (mGluRl and mGluR5) greatly reduced the response.
2、Dependence on glutamine and the role of system Xc-
The dependence of micromolar homocysteine-induced potent ERK1/2 phosphorylation on the presence of glutamine, as a precursor of glutamate, suggested the involvement of system Xc-, a conclusion, which was supported by the inhibitory effect of both DIDS and SPAP. System Xc- functions physiologically as an exchanger between intracellular glutamate and extracellular cystine. Quisqualate is both a system Xc- substrate and an agonist at non-NMDA receptors, moreover, it can "self-sensitize". Since homocysteine is both a glutamate receptor agonist and interacts with system Xc-, a similar"self-sensitization"can be expected and can explain the present results.
The dependence on glutamine, which is gradually metabolized to glutamate by a high glutaminase activity in cerebellar granule neurons, suggests that release of intracellularly accumulated homocysteine by system Xc-, is triggered by extracellular availability of glutamate after the exposure to extracellular glutamine.
3、Neurotoxicity of homocysteine
Activation of ionotropic receptors by micromolar concentrations of homocysteine are likely to contribute to neurotoxic effects of homocysteine in vivo. The present study, pointing out the crucial role of cystine-glutamate exchanger-mediated "self-sensitization"for neuronal effects of clinically relevant homocysteine concentrations, calls for additional studies whether or not pharmacological inhibition of this system. In addition, Ferrer et al. found a neuroprotective effect of ERK1/2 phosphorylation against excitotoxicity.
4、Expression of metalloproteinases in cultured astrocytes and neurons and the role of it in the EGFR transactivation
Someones used an RNase protection assay to show that among MMP-2,-9,-11,-12 and-14 were expressed, and mostly at rather low levels, in the mouse brain. But we found in the mouse brain MMP2 and MMP9 mRNA are particularly abundant. The presence of some ADAM mRNAs in the brain of a variety of animal species, demonstrated elsewhere, was confirmed for the mouse brain by Iivari Karkkainen. We found that all of 15 Mps expressed in brain in vivo were also expressed in cultured astrocytes and neurons. As compared with brain tissue, astrocytes expressed less MMP15, MMP24 and MMP25 and neurons had less MMP9. Tissue inhibitors of metalloproteinases-2(TIMP-2) can inhibit active forms of all MMPs studied to date, although TIMP-1 is a poor inhibitor of a number of the MT-MMPs. To detect whether the MT-MMP is essential for the potent shedding, we can use TIMP-1 and TIMP-2. A great deal of data has been collected regarding ectodomain shedding is predominantly mediated by ADAM. Intrerestly, we found ERK1/2 phosphorylation induced by KCl requires ADAM17 function in astrocytes, but does not require ADAM17 function in cerebellar granule neurons.
Conclusion
1、Potent homocysteine-induced ERK1/2 phosphorylation in cultured neurons via EGFR transactivation and depends on system Xc-self-sensitization.
2、We found 15 MMPs and ADAMs expressed in brain in vivo were also expressed in cultured astrocytes and neurons.
引文
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