谷氨酸受体以及兴奋性毒性研究进展

曹德茂 申宝玺 武永康 齐文涛

谷氨酸受体以及兴奋性毒性研究进展

曹德茂 申宝玺 武永康 齐文涛

在神经系统的生理和病理过程中，谷氨酸受体以及兴奋性毒性都有着重要的作用，已有多项研究表明，其分布局限,作用广泛而副作用小，被认为是治疗包括颅脑损伤在内神经系统疾病的理想靶点之一。本文通过阅读相关文献，对谷氨酸受体以及兴奋性毒性研究的历史和进展进行回顾性分析与总结。

谷氨酸受体； 兴奋性毒性； Src激酶

一、N-甲基-D-天冬氨酸受体

N-甲基-D-天冬氨酸（N-methyl-D-aspartic acid，NMDA）受体在学习、记忆和神经退行性病变等神经科学的研究中都有重要的作用。NMDA受体通道是由NR1～NR3 3个不同的亚基组成[1]。当NMDA受体被激活的时候，会有大量的阳离子流入，其中最重要的是Ca2+离子流。过高的Ca2+离子浓度会引起诸如记忆、学习等生理反应以及兴奋性毒性等病理过程。NMDA受体展示了复杂的门控通道机制，不仅要求不同配体的结合，同时还需要细胞的去极化[2]。

一般认为，NMDA受体是由2个NR1亚基和2个NR2亚基组成的异四聚体[3]。NR1亚基是由938个氨基酸构成，2个NR1亚基构成了离子通道的主体结构，并且决定了NMDA受体的主要性质[4]。甘氨酸是谷氨酸激活NMDA受体的必需辅助因子。精氨酸可以在低Ca2+浓度的时候增强NMDA受体的电流，在高浓度的时候降低NMDA受体的电流，而且可以增加NMDA受体门控通道的开放频率。除了这些配体与NMDA受体互相作用的复杂性，NMDA受体通道的很多功能都主要取决于NMDA受体通道的组成。生理上的，缺血和脑外伤等急性神经病学的刺激会改变NMDA受体的功能[5]，同时也会影响其他离子通道。

NR2亚基在NMDA受体的功能中主要起到调节作用。NR2有4个亚型，分别为NR2A、NR2B、NR2C、NR2D。其中，NR2A在脑中广泛分布，NR2B主要分布在前脑中，NR2C主要分布在小脑，而NR2D则主要分布在丘脑中。在NMDA受体复合体中[6]，NR2亚基主要调节NR1离子通道的性质。研究发现，NR2B亚基和突触后蛋白互相作用[7]，这种互相作用是通过突触后骨架蛋白实现的。

最近有研究发现NMDA受体的第3个亚基NR3主要有2种亚型，NR3A和NR3B[8]。NR3A在脑中广泛分布，而NR3B主要分布在运动神经元[9]。

二、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体

α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid，AMPA）受体、红藻氨酸受体和NMDA受体属于同一超家族，并且有25%的同源性。AMPA受体由GluR1～4 4个亚基组成，并且只需要谷氨酸盐即可激活AMPA受体[10]。AMPA受体的电流受到亚基的影响，GluR1、GluR3和GluR4增加了AMPA受体对Ca2+的通透性，而GluR2亚基则降低了对Ca2+的通透性[11]。

红藻氨酸受体是由GluR5～7和KA1～2亚基组成[12]。红藻氨酸受体和AMPA受体的特性相似。红藻氨酸受体也是只需要谷氨酸盐即可实现阳离子的内流。AMPA受体主要分布在突触后膜，但是有研究发现，红藻氨酸受体在突触前膜和突触后膜均有分布[13]。

三、代谢性谷氨酸受体

代谢性谷氨酸受体 （metabotropic glutamate receptors，mGluRs）是一个与G蛋白偶联的七跨膜结构。目前，已经发现了8个mGluRs（mGluR1～8）亚基，并且根据它们空间结构和胞内作用将其分为3组[14]。

第Ⅰ组mGluRs包括mGluR1s和mGluR5s。激活第Ⅰ组mGluRs可以通过G蛋白激活磷脂酶C，而磷脂酶C可以激活下游产生三磷酸肌醇和随后的胞内钙动员[15]。第Ⅱ组mGluRs包括mGluR2s和mGluR3s。这些mGluRs降低腺苷酸环化酶信号，导致电压依赖性钙通道的下游的抑制作用。这些受体在突触前和突触后都有分布[16]。第Ⅲ组mGluRs包括mGluR4s、mGluR6s、mGluR7s和mGluR8s[17]。第Ⅲ组mGluRs和第Ⅱ组有相似的性质，可以降低腺苷酸环化酶信号，从而激发电压依赖性钙通道下游的抑制作用，并且在突触前和突触后均有表达[18]。

当发生兴奋性毒性的时候，第Ⅰ组mGluRs可以增强NMDA受体的Ca2+流[19]。其余的由mGluR2、3、4、6、7、8亚基组成的代谢型谷氨酸受体可以抑制环磷酸腺苷[20]，减少通过NMDA受体的Ca2+流。

以上研究表明谷氨酸受体的氨基酸亚基序列可以改变Ca2+的通透性，从而影响兴奋性毒性[21]。随着对谷氨酸受体分布的研究及药理学的进展，未来也许能够更好的通过受体拮抗剂来治疗神经系统疾病。离子通道受体和胞内酶的联系也许可以为药物治疗兴奋性毒性提供一个可供选择的治疗位点[22]。

四、兴奋性毒性机制

近些年来，兴奋性毒性一直是研究热点，目前还有许多机制需要研究和阐明。其中一个重要的障碍就是谷氨酸导致的神经退行性病变的异质性[23]。细胞凋亡和细胞坏死似乎均取决于NMDA受体刺激的严重程度[24]。在活体动物中，细胞死亡的形态主要取决于神经元亚基的组成。这种不同物种之间细胞死亡的异质性在缺血模型和脑外伤模型中也是很明显的[25]。

给予较强的谷氨酸刺激之后，会出现明显的神经元坏死的病理学表现。细胞坏死的机制也许是因为线粒体功能紊乱导致的细胞能量的衰竭[26]。当给予温和的谷氨酸刺激的时候，神经元的损伤归结于不同的信号通路[27]。虽然这些信号通路中的酶包括半胱氨酸激酶、线粒体内切酶、过氧硝酸盐、聚腺苷二磷酸核糖聚合酶和甘油醛-3-磷酸脱氢酶（glyceraldehyde-3-phosphate dehydrogenase，GAPDH），但是没有哪一条信号通路可以在神经元损伤的过程中起到主要作用[28]。

五、Ca2+：兴奋性毒性的关键离子

Ca2+的内流对于谷氨酸介导的兴奋性毒性具有重要的作用。有学者认为，神经元处于高浓度的Ca2+溶液中，谷氨酸的兴奋性毒性明显加强，处于不含Ca2+离子的溶液中，兴奋性毒性明显减弱[29]。也有研究指出NMDA受体的兴奋性毒性主要取决于Ca2+的内流[30]。但是NMDA受体的兴奋性毒性主要取决于是Ca2+流入的途径而非Ca2+的内流[31]。通过NMDA受体的很小量Ca2+流即可导致大量的神经元死亡，相比之下，通过其他离子通道的大量的Ca2+流仅仅导致少量的神经元死亡[32]。进一步研究发现，NMDA受体与神经型一氧化氮合酶（neuronal nitric oxide synthase，nNOS）存在空间上的联系，而nNOS则可催化生成导致细胞毒性的NO[33]。

其他的证据表明，在谷氨酸兴奋性毒性时，大多数细胞内钙离子螯合进入线粒体[34]。这些研究表明，使用线粒体质子载体或者去除胞外溶液中Na+离子时，神经元的钙缓冲能力显著降低[35]。发生线粒体毒性时，Ca2+在线粒体内的聚积可以导致代谢性酸中毒和自由基的产生[36]。

有学者报道了在谷氨酸兴奋性毒性时，Ca2+进入胞内的动态变化过程。在海马神经元中，Ca2+进入胞内主要分为3个阶段：最初的5～10min，Ca2+持续进入胞内，随后的2 h，Ca2+在胞内聚积，最终，胞内聚积的Ca2+导致神经元的死亡。总之，增加的细胞内Ca2+通过激活一氧化氮合酶，Ca2+敏感蛋白酶以及线粒体损伤最终导致了神经元的死亡[37-39]。

六、一氧化氮

兴奋性毒性导致细胞凋亡的一个关键事件是一氧化氮（NO）的产生。有实验研究表明，体外实验中给予一氧化氮合酶抑制剂可以有效的减少谷氨酸导致的兴奋性毒性[40]。在nNOS敲除的小鼠研究中，NMDA受体介导的兴奋性毒性可以明显的减少[41]。说明nNOS生成的NOS在兴奋性毒性中起到重要作用。有实验研究了PSD95作为骨架蛋白与nNOS和NMDA受体之间的联系，这些实验表明了NMDA受体是通过PSD95和nNOS进行连接[42,43]。PSD95通过PDZ1结构域和NR2B的C端相连，同时通过PDZ2结构域和nNOS的N端相连[44,45]。在这种模块中，NMDA受体-PSD95-nNOS的空间微环境在突触后形成，而进入神经元的Ca2+则通过钙调蛋白优先激活nNOS[46]。

一旦生成，NO在胞内具有多个靶目标，同时，NO可以和自由基超氧化物歧化酶组成过氧亚硝酸盐[47]。过氧亚硝酸盐是一个强有力的氧化剂，它可以引起蛋白硝化、蛋白氧化、脂质过氧化以及DNA直接损伤，从而导致神经元的死亡[48]。最近的研究发现，NO可以和GAPDH相互作用，产生直接的神经元毒性[49]。

七、自由基

之前的研究工作已经证明自由基在谷氨酸兴奋性毒性中起到了重要的作用[50]。在甘油或者富超氧化物歧化酶的媒介中培养的小脑细胞对红藻氨酸诱导的兴奋性毒性具有抵抗作用。随后的研究发现，过表达超氧化物歧化酶的皮质神经元细胞对于谷氨酸和缺血诱导的兴奋性毒性都有保护作用[51]。多个研究小组均发现使用抗氧化剂可以在谷氨酸诱导的兴奋性毒性中起到神经元保护作用[52-55]。

实验证实发生兴奋性毒性时小脑的颗粒细胞和皮质神经元中均有自由基的产生[56]。通过使用磁共振成像，可以发现，超氧化物歧化酶的生成量和NMDA的应用具有线性关系[57]。有研究小组通过使用线粒体解偶联剂减少了自由基的生成说明自由基是在线粒体中生成[58]。

Dykens[56]首先阐明自由基的产生和Ca2+的联系，发现线粒体暴露在Ca2+和Na+离子浓度增加的环境中可以形成一个自由基生成的前馈系统。在皮质培养细胞中，Dugan等[59]发现，通过减少细胞外Ca2+，可以有效的降低NMDA受体诱导的兴奋性毒性所产生的自由基。但是，在同样的条件下，应用一氧化氮合酶抑制剂却不能减少NMDA受体诱导的兴奋性毒性所产生的自由基。Reynolds和Hastings[60]也证实了自由基的产生和Ca2+的内流具有相关性。

多个研究组均证实线粒体内自由基的生成继发于Ca2+经过NMDA受体的内流[61-63]。也就是说，Ca2+经过NMDA受体离子通道进入胞内可以引起线粒体内自由基的生成。胞质内的自由基，尤其是超氧化物，可以和其他的自由基，例如NO，共同形成强力的氧化剂。

八、NMDA受体功能的调节

Src蛋白激酶家族在中枢神经系统和周围神经系统中广泛表达[64,65]。Src蛋白激酶家族与多种类型的电压和门控通道互相作用。Src蛋白激酶家族诸如Src、Fyn可以调节神经元兴奋性和活性[66]。

Src调控乙酰胆碱受体被认为是在神经元存活调控中起到关键的作用。微管相关蛋白的富脯氨酸结构域和Fyn以及Src的SH3结构域的相互作用在神经系统疾病发生的过程中起到重要的作用。Src、Fyn和Lck在神经元的生长和少突胶质细胞的成熟中起到重要作用。缺少Fyn的小鼠体现出了严重的髓鞘缺损[67]。详细的机制研究表明Src-家族酪氨酸激酶（Src family kinases，SFKs）可以诱导NMDA受体的酪氨酸磷酸化[68-70]，导致NMDA受体功能活化。NMDA受体在突触发生和突触可塑性中具有重要的作用。血管内皮生长因子可以激活SFKs，从而可以增加NMDA受体的酪氨酸磷酸化水平[71]。

综上所述，谷氨酸受体及兴奋性毒性机制通过多渠道、多靶点发挥作用，其神经递质的调节生理过程以及脑缺血、脑创伤、癫痫发作、神经元变性疾病等病理过程均有密切的关系，随着研究的不断深入，将会为神经系统相关疾病的治疗带来新的曙光。

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Research p rogress of glutamate receptors and excitability toxicity

Cao Demao,Shen Baoxi,Wu Yongkang,QiWentao.Department of Neurosurgery,the First People’Hospital of Yangzhou,Yangzhou 225000,China

Shen Baoxi,Email:cdmaocdmao3650@163.com

The glutamate receptor and excitability toxicity play an important role in the process of physiology and pathology of the nervous system,studies have shown that it has a limited distribution but has a wide range of functions and little side effects,which have been implicated as an ideal therapeutic target following nervous system diseases,including craniocerebral injury.Retrospective analyzed the history and progress of glutamate receptors and its excitatory toxicity studies by reading relevant literature.

Glutamate receptor;Excitability toxicity;Src kinase

2017-02-12）

（本文编辑：张丽）

10.3877/cma.j.issn.2095-9141.2017.02.012

225000 扬州市第一人民医院神经外科

申宝玺，Email：cdmaocdmao3650@163.com

曹德茂,申宝玺,武永康,等.谷氨酸受体以及兴奋性毒性研究进展[J/CD].中华神经创伤外科电子杂志,2017,3(2):109-113.