CRMP-2及其新型肽段CBD3对CaV2.2调节作用机制的研究

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英文题名：The Research of the Modulation and Its Mechanism of CaV2.2by CRMP-2and Its Novel Peptide CBD3 作者：鞠维娜 论文级别：博士 学科专业名称：神经病学 中文关键词：脑衰反应调节蛋白2（CRMP-2） ; N型钙离子通道（CaV2.2） ; N-甲基-D-天冬氨酸受体（NMDARs） ; 神经性疼痛 ; 神经保护 英文关键词：CRMP-2 ; CaV2.2 ; NMDAR ; neuropathic pain ; neuroprotection 学位年度：2014 导师：吴江 学科代码：100204 学位授予单位：吉林大学 论文提交日期：2014-04-01

摘要

病理性疼痛使人们遭受着巨大的痛苦，据统计，全世界人口1/3以上遭受着持续或反复发作的疼痛折磨。在各种类型的病理性疼痛中，神经性疼痛（neuropathic pain）被视为最难攻克的难题，它是由神经系统受损或功能失调引起的病理性疼痛，是建立在神经功能、结构和递质传递改变的基础上的。自发性疼痛、痛觉过敏和异常性疼痛是神经性疼痛的主要表现。神经性疼痛的治疗非常棘手，近年来虽然在疼痛发病机制的基础研究方面突飞猛进，然而临床上的治疗手段仍然有限，并且治疗效果并不理想。目前，药物治疗仍然是该病治疗的主要手段。因此，未来的研究热点将是针对神经性疼痛的发病机制而进行的新型药物开发。
     已有大量研究表明，N型钙离子通道（CaV2.2）在感觉神经元上的功能与疼痛密切相关。由于CaV2.2的生理功能就是促进神经递质的释放，它能够调控感觉神经元内许多不同神经递质的释放，其中最感兴趣的与疼痛研究有关的是降钙素基因相关肽（CGRP）[130,296]。CGRP是一个强有力的神经肽，它能够引发血管舒张，并且它与疼痛和炎症反应有关[44,398,432]。因此，这就需要开发一种新型药物，能够拮抗CaV2.2的功能，抑制CGRP的释放，降低受伤动物模型超敏反应，从而起到治疗CaV2.2相关性神经性疼痛的目的。本研究以CRMP-2为中心，探讨了CRMP-2与CaV2.2之间的功能相互联系和作用机制，在研究过程中从CRMP-2上获取了一个新型肽段——CBD3，进一步研究了CBD3与NMDARs和CaV2.2的相互作用及其机制，阐明了CRMP-2和CBD3在调节神经递质释放中的作用，旨在为CaV2.2相关性神经痛的药物治疗开辟一条新的研究途径。
     第一部分CRMP-2对CaV2.2的调节机制的研究
     突触传递是通过一连串的蛋白-蛋白相互作用来进行调节的，而这些蛋白间的相互作用又依赖于突触前后钙离子通道的本身的定位及功能。CRMP-2被确认为是CaV2.2的潜在结合伴侣。但是到目前为止，CRMP-2在突触传递中的作用还没有被研究的很透彻。
     本研究目的主要是为了解决以下几个问题：①明确CRMP-2是否与CaV2.2进行功能性的和生化性的相互作用；②CaV2.2-CRMP-2之间的相互作用是否影响CaV2.2的功能；③CRMP-2是否能够调节突触传递。
     本研究通过一系列生物化学实验方法，免疫组织化学实验方法，神经电生理研究方法，分子生物学实验方法，动物行为学实验方法等研究得出以下研究结果：（1）CRMP-2与CaV2.2共同存在于突触和一些相同的亚细胞区室内；（2）CRMP-2与CaV2.2共同存在于一个复合物内；（3）在CRMP-2内，确定了的三个与CaV2.2发生相互作用的区域：一个位于CRMP-2的N-末端（残基94-166），另一个位于蛋白质中部（残基212-297），还有一个在CRMP-2蛋白质的C-末端附近（残基479-500），邻近微管结合域。它们分别被称为CaV结合域（CBDs）1-3。（4）在CaV2.2上确定了两个区域能够与CRMP-2结合：环1（L1）和C-末端远端部分（Ct-d）；（5）CRMP-2与CaV2.2之间的相互作用调节具有活动依赖性：即增加通过CaV2.2的钙离子内流能够增强CRMP-2-CaV2.2之间的相互作用，但当钙离子流入量达到100μM左右时，随着钙离子浓度的继续升高，CRMP-2与CaV2.2之间的相互作用强度就会逐渐下降；（6）CRMP-2-EGFP转染神经元中的钙离子电流密度显著高于EGFP转染神经元（P<0.05），而CRMP-2shRNA慢病毒感染的神经元的钙离子电流密度与CRMP-2-EGFP过表达的神经元相比，减少了80%（P<0.05）；（7）与EGFP转染神经元相比，CRMP-2-EGFP转染神经元内有更多的CaV2.2的表面蛋白表达；（8）CRMP-2-EGFP转染的神经元促使的谷氨酸释放量，与对照组中EGFP转染的神经元相比，提高了2.3倍（P<0.05）；（9）CRMP-2S522A和CRMP-2S522D转染的神经元与CRMP-2-KDR WT相比，钙离子的流入量明显减少（P<0.05）；（10）通过Cdk5的CRMP-2磷酸化导致与CRMP-2发生免疫沉淀的CaV2.2的数量明显增加（P<0.05）；（11）通过使用肽测位仪合成了一系列包含有CaV2.2结合域的长度为15个氨基酸的肽段，并从中挑选出了与CaV2.2具有最高结合潜力的一个，它就是CBD3，它能够通过CaV2.2上L1和Ct-d与CaV2.2结合；（12）将CBD3融合到HIV蛋白质TAT的转导域上，这就产生了细胞穿透性肽段TAT-CBD3；（13）TAT-CBD3通过两种途径影响CaV2.2，从而影响钙离子内流：①破坏CRMP-2与CaV2.2之间的相互作用来降低CaV2.2电流，而非通过直接靶向作用于CaV2.2；②拮抗CRMP-2诱导的钙离子通道电流增强的作用；（14）用TAT-对照培育的脊髓切片暴露于辣椒素后在iCGRP显示出了约9倍的升高，而用TAT-CBD3培育的脊髓切片与基础iCGRP水平相比则显示出了少于3倍的增长（P<0.05）；（15）在神经性疼痛动物模型中，TAT-CBD3用量为0.1mg/kg时，PWT（缩足阈值）明显下降；用量为1mg/kg时，可以完全逆转超敏反应；用量为10mg/kg时，PWT则不再升高；（16）TAT-CBD3应用1小时或7天后，对动物进行旋转实验，动物在转杆上保持直立没有影响；（17）对应用TAT-CBD3的大鼠进行Morris水迷宫测试，大鼠在用药后3小时、1天、2天和3天这4个时间段进行实验，均未显示出明显的记忆缺陷。
     主要研究结论：①CRMP-2是CaV2.2的重要调节因子：CRMP-2能够协助转运CaV2.2至膜，导致膜表面CaV2.2表达量增加，从而使CaV2.2电流增强；②CRMP-2的过表达能够促进CaV2.2介导的递质释放；③通过Cdk5在Ser-522位点的CRMP-2磷酸化是CRMP-2调节CaV2.2功能的重要决定因素；④TAT-CBD3是一种新型的CaV2.2拮抗剂，它能够抑制CGRP的释放，并能降低受伤动物模型超敏反应，因此可用于治疗CaV2.2相关的神经性疼痛等疾病，且TAT-CBD3不会造成严重的镇静作用和运动、协调功能上的缺陷，也不影响记忆提取。
     第二部分TAT-CBD3的神经保护作用及机制的研究
     通过N-甲基-D-天冬氨酸受体（NMDARs）的失控的钙内流已经与神经毒性级联反应的激活联系到了一起，最终导致细胞死亡（比如兴奋毒性）。CRMP-2被认为影响了NMDAR的转运，并且有可能与兴奋毒性后的神经元存活有关。基于以上研究，提出一个假设：来自于CRMP-2的一个肽段CBD3在面对兴奋毒性刺激时能够保护神经元。
     为了确定从CRMP-2获得的CBD3在融合了穿膜肽TAT后（TAT-CBD3）是否具有神经保护作用及其神经保护作用的机制，本研究通过使用与前一部分相似的科研技术手段，进行了大量的实验研究，得出以下结果：（1）给予谷氨酸/丝氨酸刺激后，暴露在TAT-CBD3的神经元与暴露在TAT-对照的神经元相比，CRMP-2裂解减少约70%（P<0.05）；若给予离子霉素刺激，TAT-CBD3不改变CRMP-2的裂解情况；在体外，TAT-CBD3不会改变钙蛋白酶的活性和CRMP-2的裂解；（2）TAT-CBD3在3μM和1μM的情况下，对谷氨酸/丝氨酸产生的兴奋性毒性的神经保护作用明显（P<0.05）；用10μM TAT-CBD3预处理神经元后，给予谷氨酸/丝氨酸刺激，发现刺激后0.5小时所表现的神经保护作用具有统计学意义（P<0.05）；（3）用TAT-对照对神经元进行预处理后，给予刺激，CRMP-2shRNA慢病毒转导的神经元与阴性shRNA处理的神经元相比，细胞存活率明显增加（p <0.05）；在转导了CRMP-2shRNA并在兴奋性毒素刺激前用TAT-CBD3预处理的神经元中，观察到了完全的神经保护作用；对于转导了阴性shRNA慢病毒的神经元，TAT-CBD3并未显示出完全的神经保护作用；（4）用ω-CTX处理后，无论是用还是不用谷氨酸/丝氨酸刺激神经元，都对CRMP-2的裂解没有影响；ω-CTX对CaV2.2的阻断作用没有明显地改变神经元在谷氨酸/丝氨酸刺激后的存活；（5）用溶质、TAT-对照或TAT-CBD3预处理神经元10分钟后，给予谷氨酸/甘氨酸刺激，TAT-CBD3处理组与其他两个组相比，其胞质内钙离子浓度（[Ca2+]c）显著降低（P<0.05），平均曲线下面积分别减少了78%和75%（P<0.05）；（6）当对神经元使用50μM NMDA时观测到了[Ca2+]c的尖锐增加峰，并且在移除NMDA后恢复到基线。当在NMDA三次刺激的间期使用溶质（DMSO）时，未观察到[Ca2+]c幅度的改变。然而，当在该间期使用10μMTAT-CBD3培育神经元时，NMDA的第二次和第三次反应大大衰减了。对于溶剂处理的神经元，NMDA诱导的第二和第一钙离子峰比值（P2/P1）为1.05±0.09，而10μMTAT-CBD3孵育将P2/P1比值减小到0.25±0.03。TAT-CBD3处理神经元的第三和第一钙离子峰(P3/P1)比值为0.33±0.03，TAT-CBD3和100μM AP-5共同使用的P2/P1比值0.19±0.03，P3/P1比值为0.93±0.08；（7）将CRMP-2siRNA+GFP转染入5DIV的神经元，然后使用双脉冲NMDA方案在7DIV进行钙成像。与未转染的对照组相比（P2/P1=0.29±0.06），转染了CRMP-2siRNA的神经元显示出TAT-CBD3对NMDAR介导的钙离子内流抑制作用减弱（P2/P1=0.60±0.09，p <0.05）；（8）通过分别使用NR2B和NR2A的特异性阻断剂Ifenprodil和Peaqx对皮层神经元预处理10分钟，然后用谷氨酸/甘氨酸刺激神经元30分钟，在7DIV中发现Ifenprodil而非Peaqx能完全阻止谷氨酸/甘氨酸诱导的毒性（P<0.05）；（9）用10μM TAT-对照孵育神经元后与溶质孵育的神经元相比20分钟时荧光没有发生明显变化。与此相反，孵育10μM TAT-CBD3引起NR2B-SEP荧光减少约60%（P<0.05）；（10）在肽段/药物使用后20分钟观察到，NMDAR拮抗剂MK801（50μM）和10μM的TAT-CBD3的共同应用完全阻止了TAT-CBD3诱导的NR2B-SEP荧光降低，单独用50μM MK801处理对NR2B-SEP荧光没有影响；（11）给予50μM NMDA刺激2秒，两次刺激之间的时间间隔为30秒。在5分钟稳定的NMDA刺激反应（峰值变化<5%）后，向神经元灌注10μM TAT-CBD3。TAT-CBD3诱导快速强烈的NMDA电流的抑制作用，并在5分钟后阻断约~70%。使用无TAT-CBD3的电解液冲洗，在10分钟后部分NMDA电流恢复。
     主要研究结论：①TAT-CBD3通过减少谷氨酸刺激下的钙离子内流，阻止α-血影蛋白和CRMP-2的钙蛋白酶裂解；②CRMP-2基因沉默本身具有神经保护作用，它不止和谷氨酸介导的神经毒性有关，还能有效的针对性的阻止兴奋性毒性介导的神经元死亡；③TAT-CBD3是一种新型神经保护肽，可通过抑制NMDARs和诱导树突棘NMDAR内在化，最终导致谷氨酸诱导的DCD和NMDA刺激的钙离子内流减少，从而有效的治疗慢性神经性疼痛以及卒中或其他神经性损害后的兴奋性毒性。
Millions of people were suffered from pathological pain, according to statistics, one thirdof the people in the world were suffering from the persistent or repetitive pain. Neuropathicpain is the hardest problem to solve in various kinds of pathological pain. It is a kind ofpathological pain which is due to the insult or dysfunction of nervous system and is based onthe change of nervous function, structure and neurotransmission. Spontaneous pain,hyperpathia and allodynia are the major performance of the neuropathic pain. The treatmentof the neuropathic pain is thorny, although the fundamental research of pathogenesis areadvancing by leaps and bounds in these years, it is still limited and unsatisfactory in thetreatment. At present, medication treatment is still the main treatment means. Therefore, theresearch hotspot in the future will be the development of new drugs targeted the mechanismof neuropathic pain.
     A lot of research have suggested that the function of CaV2.2is closely related to the painin sensory neurons. The physiological function of CaV2.2facilitate the release ofneurotransmitter, it can regulate various diverse neurotransmission in which CGRP is the mostinterested. CGRP is a powerful peptide which can cause vasodilatation and have closelyrelation with pain and inflammation. Therefore, a novel medication is required to antagonizethe function of CaV2.2, inhibit the release of CGRP and decrease hypersensitivity of theinjured animal model, consequently achieve the goal to treat the CaV2.2related pain. Myresearch that focused on the CRMP-2discusses the interaction and its mechanism of CRMP-2and CaV2.2. I found a new peptide which is derived from CRMP-2during the research, andfurther study the interaction and its mechanism of CBD3and CaV2.2or NMDARs,illustrating the function of CRMP-2and CBDs in the regulation of neurotransmission, whichis aimed to develop a new research method to treat the CaV2.2related neuropathic pain.
     Chapter one: The research of the regulation between CRMP-2and CaV2.2
     Synaptic transmission is coordinated by a litany of protein-protein interactions that relyon the proper localization and function of pre-and post-synaptic Ca2+channels. The axonalguidance/specification collapsin response mediator protein-2(CRMP-2) was identified as a potential partner of the pre-synaptic N-type voltage-gated Ca2+channel (CaV2.2). So far, it isstill unclear that the function of CRMP-2in neurotransmission.
     The research is aimed to solve several problems:①d etermine if CRMP-2interactsfunctionally and biochemically with CaV2.2;②d etermine if the interaction between CRMP-2and CaV2.2affects the function of CaV2.2;③d etermine if CRMP-2regulate theneurotransmission.
     The research obtained several results by various study, including biochemical method,immunohistochemical method, electrophysiological method, molecular biological method andanimal behavior test.（1）CRMP-2and CaV2.2are co-localization in the synapse and somesubcellular compartment;（2）CRMP-2and CaV2.2co-exist in a complex;（3）WithinCRMP-2, three regions of interactions were determined: a region in the CRMP-2N-terminus(residues94-166), a region in the middle of the protein (residues212–297), and one near theC-terminus of the CRMP-2protein (residues479-500), proximal to the microtubule bindingdomain. These regions were designated CaV binding domains (CBDs)1–3;（4）WithinCaV2.2, CRMP-2bound two regions on CaV2.2: loop1(L1) and the distal part of theC-terminus (Ct-d);（5）CRMP-2-CaV2.2interaction is activity dependence: The increase ofCa2+influx by CaV2.2enhanced the CRMP-2-CaV2.2interaction. But when theconcentration of Ca2+influx reach100μM, the strength of CRMP-2and CaV2.2interaction isdecreasing according to this;（6）The Ca2+current density was significantly higher inCRMP-2-EGFP-transfected neurons than in EGFP neurons.(P<0.05), and the infection of12DIV hippocampal neurons with CRMP-2shRNA lentivirus for seven days reduced Ca2+currents to2.9±0.4pA/pF (n=9); an~80%reduction compared to CRMP-2–EGFPover-expressing neurons(P<0.05);（7）Immunoblotting with CaV2.2for streptavidin-enrichedcomplexes from biotinylated neurons showed increased CaV2.2surface expression inCRMP-2-EGFP expressing neurons compared to EGFP neurons;（8）Exposing hippocampalneurons transfected with EGFP to30mM KCl stimulated glutamate release by about3.5-foldfrom a basal level. In CRMP-2-EGFP over-expressing neurons,30mM KCl stimulatedglutamate release by about8-fold from a basal level (p<0.001vs. EGFP). This shows thatCRMP-2can augment glutamate release by2.3-fold over control EGFP-transfected cells;（9） CRMP-2S522A and CRMP-2S522D-transfected neurons compared to CRMP-2-KDRWT-transfected neurons, have lower Ca2+influx(P<0.05);（10）The phosphorylation ofCRMP-2by Cdk5leads to a significant increase in the amount of CaV2.2bound to theimmunoprecipitated CRMP-2(P<0.05);（11）To develop a reagent to disrupt the interactionof CRMP-2with the CaV2.2complex in vivo, a series of overlapping15-amino-acid peptideswere synthesized covering the entire length of CRMP-2using a robotic peptide spotter. Thepeptide found to have the highest binding potential for CaV2.2was a15amino acid portion ofthe previously identified CBD3sequence;（12）In order to facilitate the penetrance of theCBD3peptide inside of cell for future studies the CBD3peptide was fused to the transductiondomain of the HIV protein TAT. This yielded the cell penetrating peptides TAT-CBD3;（13）TAT-CBD3affects the CaV2.2to inhibit the Ca2+influx by two means:①T AT-CBD3decreases the CaV2.2current by destroying the CRMP-2-CaV2.2interaction, but not bytargeting CaV2.2；②T AT-CBD3antagonizes the CRMP-2induced Ca2+current enhancement;（14）Slices incubated with TAT-Control displayed a~9fold increase in iCGRP in response toCapsaicin exposure whereas those incubated with TAT-CBD3displayed less than a3foldincrease compared to basal iCGRP levels(P<0.05);（15）A significant increase in PWT wasseen with injection of TAT-CBD3at0.1mg/kg and complete reversal of hypersensitivity wasaccomplished by1mg/kg. No additional increase in PWT was observed when TAT-CBD3was increased to10mg/kg;（16）TAT-CBD3, at doses as high as50mg/kg, showed no effecton the animals’ ability to stay upright on the rotating rod at1h or up to7days later.;（17）Following TAT-CBD3injection animals were tested in the Morris water maze at3h,1,2, and3days. Animals showed no significant deficit in latency to reach the platform at any of thesetime points.
     Main conclusion:①CRMP-2is the important regulator to CaV2.2：CRMP-2canfacilitate to transfer CaV2.2to membrane, lead to the increase of CaV2.2expression in thesurface membrane, then cause the enhancement of the CaV2.2current;②Theoverexpression of CRMP-2can facilitate the CaV2.2induced neurotransmitter release;③The phosphorylation of CRMP-2by Cdk5at Ser-522is the important determinant to theregulation of CaV2.2;④T AT-CBD3is a novel antagonist of CaV2.2, it can inhibit the release of CGRP, and decrease the hypersensitivity of the injured animal models, therefore itcan be used to treat the CaV2.2related neuropathic pain and so on, additionally TAT-CBD3will not cause a sever sedation and deficient in the function of motor and coordinate as wellas the memory extracted.Chapter2: The research of the neuroprotection and its mechanism of TAT-CBD3
     Unchecked Ca2+influx via N-methyl-D-aspartate receptors (NMDARs) has been linkedto activation of neurotoxic cascades culminating in cell death (i.e. excitotoxicity). CRMP-2was suggested to affect NMDAR trafficking and possibly involved in neuronal survivalfollowing excitotoxicity. Based upon these studies, I hypothesized that a peptide fromCRMP2could preserve neurons in the face of excitotoxic challenges.
     In order to determine the neuroprotection and its mechanism of TAT-CBD3which isderived from CRMP-2and fused to cell penetrating peptide TAT, I did a bunch of studies bythe similar methods as mentioned above, and obtain several results:（1）At24hours postglutamate induced stimulation, neurons exposed to TAT-CBD3had~70%less cleavedCRMP-2compared to neurons exposed to TAT-Control(P<0.05); TAT-CBD3does not altercleavage of CRMP-2in response to Ionomycin；TAT-CBD3does not alter in vitro cleavage ofCRMP-2and activation of calpain;（2）Neurons pre-treated for10min with10μMTAT-CBD3and then stimulated with Glu/Ser completely survived the excitotoxic treatment.Significant neuroprotection by TAT-CBD3was evident at3and1μM but not at0.1μM(P<0.05); To test if TAT-CBD3is neuroprotective following stimulation, neurons weretreated with10μM TAT-CBD3for10minutes at0.5,1,2,3, and6hours after Glu/Serstimulation and cell viability measured as described. Except for modest, but statisticallysignificant, neuroprotection at0.5hour following stimulation, TAT-CBD3was not effective atlater times(P<0.05)（；3）CRMP-2shRNA lentiviral–transduced neurons exhibited a significantincrease in cell viability following stimulation compared to scramble shRNA treated neuronswhen pre-treated with TAT-Control(p<0.05). Complete neuroprotection was observed inneurons transduced with CRMP-2shRNA lentivirus and pre-treated with TAT-CBD3prior toexcitotoxic challenge. That neurons transduced with scramble shRNA lentivirus did notexhibit complete neuroprotection with TAT-CBD3;（4）Lysates were then made24hr following stimulation and CRMP-2cleavage was assessed by immunoblotting. Treatmentwith ω-CTX with or without stimulation by Glu/Ser had no effect on CRMP-2cleavage；Theblockade of CaV2.2with ω-CTX did not significantly alter neuronal survival of neuronsfollowing Glu/Ser；（5）Both vehicle and TAT-Control displayed similar increases in [Ca2+]cduring the prolonged exposure to glutamate. In contrast, TAT-CBD3showed a significantdecrease in [Ca2+]ccompared to vehicle and TAT-Control（P<0.05）. The changes in [Ca2+]cfollowing glutamate stimulation, represented by average area under the curve (AUC), wasdecreased by78%and75%compared to that observed in TAT-Control and vehicle-treatedneurons, respectively（P<0.05）;（6）A sharp increase in [Ca2+]cwas observed when NMDAis applied, which returned to baseline upon NMDA removal. When vehicle (DMSO) wasapplied during the interim between the three NMDA stimulations, no change in [Ca2+]camplitude was observed. However, when neurons were treated with10μM TAT-CBD3duringthis interim period, the second and third responses to NMDA were strongly attenuated. Theratio of the2nd to1st NMDA-induced Ca2+peak (P2/P1) for vehicle treated neurons was1.05±0.09whereas incubation with10μM TAT-CBD3reduced the P2/P1ratio to0.25±0.03. Theratio of the3rd to1st Ca2+peak (P3/P1) for TAT-CBD3neurons was0.33±0.03.Co-application of TAT-CBD3with100μM AP-5led to a P2/P1ratio of0.19±0.03and aP3/P1of0.93±0.08;（7）Neurons were transfected with CRMP-2siRNA+GFP at5DIVand then Ca2+imaging was performed using a two-pulse NMDA protocol at7DIV. Neuronstreated with CRMP-2siRNA exhibited reduced inhibition of NMDAR-mediated Ca2+-influxby TAT-CBD3(P2/P1=0.60±0.09) vs. untransfected controls (P2/P1=0.29±0.06, p <0.05);（8）I employed the use of the NR2B and NR2A specific blockers Ifenprodil and Peaqxrespectively to accomplish this goal. Cortical neurons were treated for10minutes prior tostimulation and throughout stimulation with200μM glutamate and20μM glycine for30min.At7DIV it was found that Ifenprodil, but not Peaqx, was able to completely preventGlu/Gly-induced toxicity（P<0.05）;（9）Incubation of neurons with10μM TAT-Controlshowed no significant change in fluorescence at20minutes compared to vehicle. In contrast,incubation with10μM TAT-CBD3caused a~60%reduction in NR2B-SEPfluorescence(P<0.05）;（10）Concomitant addition of the NMDAR antagonist MK801(50μM) with10μM TAT-CBD3completely prevented the TAT-CBD3-induced reduction inNR2B-SEP fluorescence observed at20minutes following peptide/drug application.Treatment with50μM MK801alone had no effect on NR2B-SEP fluorescence;（11）NMDAR currents were recorded from rat hippocampal neuron somas (DIV7-11) usingwhole-cell voltage-clamp electrophysiology by stimulating with50μM NMDA for2secondswith a30second interval between stimulations. Following5minutes of stableNMDA-stimulated responses neurons were perfused with10μM TAT-CBD3. TAT-CBD3induced rapid and strong inhibition of NMDA currents with~70%block after5minutes.Washout with bath solution lacking TAT-CBD3led to partial recovery of NMDA currentsafter10minutes.
     Main conclusion:①T AT-CBD3inhibits the α-spectrin and CRMP-2calpain cleavage bydecreasing the glutamate-induced Ca2+influx;②CRMP-2knockdown is neuroprotective, andnot only involved in glutamate-induced exitotoxcity, but also effectively targetes to preventexitotoxcity-induced cell death;③T AT-CBD3is a novel neuroprotective peptide, it leads tothe decrease of glutamate-induced DCD and NMDA-stimulated Ca2+influx by inhibiting theNMDARs or inducing NMDAR in dendrite spine internalization, then it can be used to treatthe chronic neuropathic pain and excitotoxicity following stroke or other neuronal insults.

引文

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