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      谷氨酸受體以及興奮性毒性研究進展

      2017-01-10 14:37:55曹德茂申寶璽武永康齊文濤
      關(guān)鍵詞:興奮性亞基谷氨酸

      曹德茂 申寶璽 武永康 齊文濤

      谷氨酸受體以及興奮性毒性研究進展

      曹德茂 申寶璽 武永康 齊文濤

      在神經(jīng)系統(tǒng)的生理和病理過程中,谷氨酸受體以及興奮性毒性都有著重要的作用,已有多項研究表明,其分布局限,作用廣泛而副作用小,被認為是治療包括顱腦損傷在內(nèi)神經(jīng)系統(tǒng)疾病的理想靶點之一。本文通過閱讀相關(guān)文獻,對谷氨酸受體以及興奮性毒性研究的歷史和進展進行回顧性分析與總結(jié)。

      谷氨酸受體; 興奮性毒性; Src激酶

      一、N-甲基-D-天冬氨酸受體

      N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid,NMDA)受體在學習、記憶和神經(jīng)退行性病變等神經(jīng)科學的研究中都有重要的作用。NMDA受體通道是由NR1~NR3 3個不同的亞基組成[1]。當NMDA受體被激活的時候,會有大量的陽離子流入,其中最重要的是Ca2+離子流。過高的Ca2+離子濃度會引起諸如記憶、學習等生理反應(yīng)以及興奮性毒性等病理過程。NMDA受體展示了復雜的門控通道機制,不僅要求不同配體的結(jié)合,同時還需要細胞的去極化[2]。

      一般認為,NMDA受體是由2個NR1亞基和2個NR2亞基組成的異四聚體[3]。NR1亞基是由938個氨基酸構(gòu)成,2個NR1亞基構(gòu)成了離子通道的主體結(jié)構(gòu),并且決定了NMDA受體的主要性質(zhì)[4]。甘氨酸是谷氨酸激活NMDA受體的必需輔助因子。精氨酸可以在低Ca2+濃度的時候增強NMDA受體的電流,在高濃度的時候降低NMDA受體的電流,而且可以增加NMDA受體門控通道的開放頻率。除了這些配體與NMDA受體互相作用的復雜性,NMDA受體通道的很多功能都主要取決于NMDA受體通道的組成。生理上的,缺血和腦外傷等急性神經(jīng)病學的刺激會改變NMDA受體的功能[5],同時也會影響其他離子通道。

      NR2亞基在NMDA受體的功能中主要起到調(diào)節(jié)作用。NR2有4個亞型,分別為NR2A、NR2B、NR2C、NR2D。其中,NR2A在腦中廣泛分布,NR2B主要分布在前腦中,NR2C主要分布在小腦,而NR2D則主要分布在丘腦中。在NMDA受體復合體中[6],NR2亞基主要調(diào)節(jié)NR1離子通道的性質(zhì)。研究發(fā)現(xiàn),NR2B亞基和突觸后蛋白互相作用[7],這種互相作用是通過突觸后骨架蛋白實現(xiàn)的。

      最近有研究發(fā)現(xiàn)NMDA受體的第3個亞基NR3主要有2種亞型,NR3A和NR3B[8]。NR3A在腦中廣泛分布,而NR3B主要分布在運動神經(jīng)元[9]。

      二、α-氨基-3-羥基-5-甲基-4-異惡唑丙酸受體

      α-氨基-3-羥基-5-甲基-4-異惡唑丙酸(α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid,AMPA)受體、紅藻氨酸受體和NMDA受體屬于同一超家族,并且有25%的同源性。AMPA受體由GluR1~4 4個亞基組成,并且只需要谷氨酸鹽即可激活AMPA受體[10]。AMPA受體的電流受到亞基的影響,GluR1、GluR3和GluR4增加了AMPA受體對Ca2+的通透性,而GluR2亞基則降低了對Ca2+的通透性[11]。

      紅藻氨酸受體是由GluR5~7和KA1~2亞基組成[12]。紅藻氨酸受體和AMPA受體的特性相似。紅藻氨酸受體也是只需要谷氨酸鹽即可實現(xiàn)陽離子的內(nèi)流。AMPA受體主要分布在突觸后膜,但是有研究發(fā)現(xiàn),紅藻氨酸受體在突觸前膜和突觸后膜均有分布[13]。

      三、代謝性谷氨酸受體

      代謝性谷氨酸受體 (metabotropic glutamate receptors,mGluRs)是一個與G蛋白偶聯(lián)的七跨膜結(jié)構(gòu)。目前,已經(jīng)發(fā)現(xiàn)了8個mGluRs(mGluR1~8)亞基,并且根據(jù)它們空間結(jié)構(gòu)和胞內(nèi)作用將其分為3組[14]。

      第Ⅰ組mGluRs包括mGluR1s和mGluR5s。激活第Ⅰ組mGluRs可以通過G蛋白激活磷脂酶C,而磷脂酶C可以激活下游產(chǎn)生三磷酸肌醇和隨后的胞內(nèi)鈣動員[15]。第Ⅱ組mGluRs包括mGluR2s和mGluR3s。這些mGluRs降低腺苷酸環(huán)化酶信號,導致電壓依賴性鈣通道的下游的抑制作用。這些受體在突觸前和突觸后都有分布[16]。第Ⅲ組mGluRs包括mGluR4s、mGluR6s、mGluR7s和mGluR8s[17]。第Ⅲ組mGluRs和第Ⅱ組有相似的性質(zhì),可以降低腺苷酸環(huán)化酶信號,從而激發(fā)電壓依賴性鈣通道下游的抑制作用,并且在突觸前和突觸后均有表達[18]。

      當發(fā)生興奮性毒性的時候,第Ⅰ組mGluRs可以增強NMDA受體的Ca2+流[19]。其余的由mGluR2、3、4、6、7、8亞基組成的代謝型谷氨酸受體可以抑制環(huán)磷酸腺苷[20],減少通過NMDA受體的Ca2+流。

      以上研究表明谷氨酸受體的氨基酸亞基序列可以改變Ca2+的通透性,從而影響興奮性毒性[21]。隨著對谷氨酸受體分布的研究及藥理學的進展,未來也許能夠更好的通過受體拮抗劑來治療神經(jīng)系統(tǒng)疾病。離子通道受體和胞內(nèi)酶的聯(lián)系也許可以為藥物治療興奮性毒性提供一個可供選擇的治療位點[22]。

      四、興奮性毒性機制

      近些年來,興奮性毒性一直是研究熱點,目前還有許多機制需要研究和闡明。其中一個重要的障礙就是谷氨酸導致的神經(jīng)退行性病變的異質(zhì)性[23]。細胞凋亡和細胞壞死似乎均取決于NMDA受體刺激的嚴重程度[24]。在活體動物中,細胞死亡的形態(tài)主要取決于神經(jīng)元亞基的組成。這種不同物種之間細胞死亡的異質(zhì)性在缺血模型和腦外傷模型中也是很明顯的[25]。

      給予較強的谷氨酸刺激之后,會出現(xiàn)明顯的神經(jīng)元壞死的病理學表現(xiàn)。細胞壞死的機制也許是因為線粒體功能紊亂導致的細胞能量的衰竭[26]。當給予溫和的谷氨酸刺激的時候,神經(jīng)元的損傷歸結(jié)于不同的信號通路[27]。雖然這些信號通路中的酶包括半胱氨酸激酶、線粒體內(nèi)切酶、過氧硝酸鹽、聚腺苷二磷酸核糖聚合酶和甘油醛-3-磷酸脫氫酶(glyceraldehyde-3-phosphate dehydrogenase,GAPDH),但是沒有哪一條信號通路可以在神經(jīng)元損傷的過程中起到主要作用[28]。

      五、Ca2+:興奮性毒性的關(guān)鍵離子

      Ca2+的內(nèi)流對于谷氨酸介導的興奮性毒性具有重要的作用。有學者認為,神經(jīng)元處于高濃度的Ca2+溶液中,谷氨酸的興奮性毒性明顯加強,處于不含Ca2+離子的溶液中,興奮性毒性明顯減弱[29]。也有研究指出NMDA受體的興奮性毒性主要取決于Ca2+的內(nèi)流[30]。但是NMDA受體的興奮性毒性主要取決于是Ca2+流入的途徑而非Ca2+的內(nèi)流[31]。通過NMDA受體的很小量Ca2+流即可導致大量的神經(jīng)元死亡,相比之下,通過其他離子通道的大量的Ca2+流僅僅導致少量的神經(jīng)元死亡[32]。進一步研究發(fā)現(xiàn),NMDA受體與神經(jīng)型一氧化氮合酶(neuronal nitric oxide synthase,nNOS)存在空間上的聯(lián)系,而nNOS則可催化生成導致細胞毒性的NO[33]。

      其他的證據(jù)表明,在谷氨酸興奮性毒性時,大多數(shù)細胞內(nèi)鈣離子螯合進入線粒體[34]。這些研究表明,使用線粒體質(zhì)子載體或者去除胞外溶液中Na+離子時,神經(jīng)元的鈣緩沖能力顯著降低[35]。發(fā)生線粒體毒性時,Ca2+在線粒體內(nèi)的聚積可以導致代謝性酸中毒和自由基的產(chǎn)生[36]。

      有學者報道了在谷氨酸興奮性毒性時,Ca2+進入胞內(nèi)的動態(tài)變化過程。在海馬神經(jīng)元中,Ca2+進入胞內(nèi)主要分為3個階段:最初的5~10min,Ca2+持續(xù)進入胞內(nèi),隨后的2 h,Ca2+在胞內(nèi)聚積,最終,胞內(nèi)聚積的Ca2+導致神經(jīng)元的死亡。總之,增加的細胞內(nèi)Ca2+通過激活一氧化氮合酶,Ca2+敏感蛋白酶以及線粒體損傷最終導致了神經(jīng)元的死亡[37-39]。

      六、一氧化氮

      興奮性毒性導致細胞凋亡的一個關(guān)鍵事件是一氧化氮(NO)的產(chǎn)生。有實驗研究表明,體外實驗中給予一氧化氮合酶抑制劑可以有效的減少谷氨酸導致的興奮性毒性[40]。在nNOS敲除的小鼠研究中,NMDA受體介導的興奮性毒性可以明顯的減少[41]。說明nNOS生成的NOS在興奮性毒性中起到重要作用。有實驗研究了PSD95作為骨架蛋白與nNOS和NMDA受體之間的聯(lián)系,這些實驗表明了NMDA受體是通過PSD95和nNOS進行連接[42,43]。PSD95通過PDZ1結(jié)構(gòu)域和NR2B的C端相連,同時通過PDZ2結(jié)構(gòu)域和nNOS的N端相連[44,45]。在這種模塊中,NMDA受體-PSD95-nNOS的空間微環(huán)境在突觸后形成,而進入神經(jīng)元的Ca2+則通過鈣調(diào)蛋白優(yōu)先激活nNOS[46]。

      一旦生成,NO在胞內(nèi)具有多個靶目標,同時,NO可以和自由基超氧化物歧化酶組成過氧亞硝酸鹽[47]。過氧亞硝酸鹽是一個強有力的氧化劑,它可以引起蛋白硝化、蛋白氧化、脂質(zhì)過氧化以及DNA直接損傷,從而導致神經(jīng)元的死亡[48]。最近的研究發(fā)現(xiàn),NO可以和GAPDH相互作用,產(chǎn)生直接的神經(jīng)元毒性[49]。

      七、自由基

      之前的研究工作已經(jīng)證明自由基在谷氨酸興奮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養(yǎng)的小腦細胞對紅藻氨酸誘導的興奮性毒性具有抵抗作用。隨后的研究發(fā)現(xiàn),過表達超氧化物歧化酶的皮質(zhì)神經(jīng)元細胞對于谷氨酸和缺血誘導的興奮性毒性都有保護作用[51]。多個研究小組均發(fā)現(xiàn)使用抗氧化劑可以在谷氨酸誘導的興奮性毒性中起到神經(jīng)元保護作用[52-55]。

      實驗證實發(fā)生興奮性毒性時小腦的顆粒細胞和皮質(zhì)神經(jīng)元中均有自由基的產(chǎn)生[56]。通過使用磁共振成像,可以發(fā)現(xiàn),超氧化物歧化酶的生成量和NMDA的應(yīng)用具有線性關(guān)系[57]。有研究小組通過使用線粒體解偶聯(lián)劑減少了自由基的生成說明自由基是在線粒體中生成[58]。

      Dykens[56]首先闡明自由基的產(chǎn)生和Ca2+的聯(lián)系,發(fā)現(xiàn)線粒體暴露在Ca2+和Na+離子濃度增加的環(huán)境中可以形成一個自由基生成的前饋系統(tǒng)。在皮質(zhì)培養(yǎng)細胞中,Dugan等[59]發(fā)現(xiàn),通過減少細胞外Ca2+,可以有效的降低NMDA受體誘導的興奮性毒性所產(chǎn)生的自由基。但是,在同樣的條件下,應(yīng)用一氧化氮合酶抑制劑卻不能減少NMDA受體誘導的興奮性毒性所產(chǎn)生的自由基。Reynolds和Hastings[60]也證實了自由基的產(chǎn)生和Ca2+的內(nèi)流具有相關(guān)性。

      多個研究組均證實線粒體內(nèi)自由基的生成繼發(fā)于Ca2+經(jīng)過NMDA受體的內(nèi)流[61-63]。也就是說,Ca2+經(jīng)過NMDA受體離子通道進入胞內(nèi)可以引起線粒體內(nèi)自由基的生成。胞質(zhì)內(nèi)的自由基,尤其是超氧化物,可以和其他的自由基,例如NO,共同形成強力的氧化劑。

      八、NMDA受體功能的調(diào)節(jié)

      Src蛋白激酶家族在中樞神經(jīng)系統(tǒng)和周圍神經(jīng)系統(tǒng)中廣泛表達[64,65]。Src蛋白激酶家族與多種類型的電壓和門控通道互相作用。Src蛋白激酶家族諸如Src、Fyn可以調(diào)節(jié)神經(jīng)元興奮性和活性[66]。

      Src調(diào)控乙酰膽堿受體被認為是在神經(jīng)元存活調(diào)控中起到關(guān)鍵的作用。微管相關(guān)蛋白的富脯氨酸結(jié)構(gòu)域和Fyn以及Src的SH3結(jié)構(gòu)域的相互作用在神經(jīng)系統(tǒng)疾病發(fā)生的過程中起到重要的作用。Src、Fyn和Lck在神經(jīng)元的生長和少突膠質(zhì)細胞的成熟中起到重要作用。缺少Fyn的小鼠體現(xiàn)出了嚴重的髓鞘缺損[67]。詳細的機制研究表明Src-家族酪氨酸激酶(Src family kinases,SFKs)可以誘導NMDA受體的酪氨酸磷酸化[68-70],導致NMDA受體功能活化。NMDA受體在突觸發(fā)生和突觸可塑性中具有重要的作用。血管內(nèi)皮生長因子可以激活SFKs,從而可以增加NMDA受體的酪氨酸磷酸化水平[71]。

      綜上所述,谷氨酸受體及興奮性毒性機制通過多渠道、多靶點發(fā)揮作用,其神經(jīng)遞質(zhì)的調(diào)節(jié)生理過程以及腦缺血、腦創(chuàng)傷、癲癇發(fā)作、神經(jīng)元變性疾病等病理過程均有密切的關(guān)系,隨著研究的不斷深入,將會為神經(jīng)系統(tǒng)相關(guān)疾病的治療帶來新的曙光。

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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)

      (本文編輯:張麗)

      10.3877/cma.j.issn.2095-9141.2017.02.012

      225000 揚州市第一人民醫(yī)院神經(jīng)外科

      申寶璽,Email:cdmaocdmao3650@163.com

      曹德茂,申寶璽,武永康,等.谷氨酸受體以及興奮性毒性研究進展[J/CD].中華神經(jīng)創(chuàng)傷外科電子雜志,2017,3(2):109-113.

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