[生物医药论文精品]钙超载的危害和新型钙阻断剂的研发

钙超载的危害和新型钙阻断剂的研发摘要目的介绍细胞钙超载的危害及新型钙阻断剂的研发和应用。方法对近期文献进行综述。结果细胞內钙超载对人体有害，可导致高血压，神经元损伤包括癫痫、偏头痛、慢性神经性头痛、阿尔茨海默病，胰腺炎，细胞凋亡等，己分别研发出新型的钙阻断剂，包括同时作用于L及T型钙通道的阻断剂，作用于钙通道A1亚基的阻断剂，作用于胞內IPA2受体的阻断剂等且取得疗效。结论在我国应加强研究钙超载的危害及新型鈣阻断剂的研发。会给分子治疗学增添新的亮点。关键词钙超载疾病钙阻断剂新型CALCG76G88G80G82G89G72G85LG82AG71AG81G71G81G72G90G87G92G83G72CALCG76G88G80AG81G87AG74G82G81G76G86G87G59G88G72G84G88AG81G16G73G88G15G58AG81G74G93G75G72G81G16G74AG81G74G36G69G86G87G85ACG87G50G69G77G72CG87G43AG85G80G73G88LG72G73G73G72CG87G82G73CG72LLG88LAG85CALCG76G88G80G82G89G72G85LG82AG71AG81G71G81G72G90CALCG76G88G80AG81G87AG74G82G81G76G86G87G86G90G72G85G72G76G81G87G85G82G71G88CG72G71G17G48G72G87G75G82G71LG76G87G72G85ACG87G88G85G72G86G88G83G71AG87G72G71G90G72G85G72G86G88G80G80AG85G76G93G72G71G17G53G72G86G88LG87。TG75G72CG72LLG88LAG85CALCG76G88G80G82G89G72G85LG82AG71G76G86G75AG85G80G73G88LG73G82G85G75G88G80AG81，G90G75G76CG75CAG81G76G81G71G88CG72G75G92G83G72G85G87G72G81G86G76G82G81，G76G80G83AG76G85G82G73G81G72G88G85G82G81G76G81CLG88G71G76G81G74G72G83LG72G83G86G92，G80G76G74G85AG76G81G72，G81G72G88G85G82G83AG87G75G76CG83AG76G81，AG81G71G36LG93G75G72G76G80G72G85G255G86G71G76G86G72AG86G72，G83AG81CG85G72G87G76G87G76G86，AG81G71CG72LLAG83G82G83G82G87G82G86G76G86AG81G71G86G82G82G81。G39G76G73G73G72G85G72G81G87G81G72G90G87G92G83G72CALCG76G88G80AG81G87AG74G82G81G76G86G87G86G90G72G85G72G71G72G86G76G74G81G72G71AG81G71AG83G83LG76G72G71G86G88CG75AG86LAG81G71TG87G92G83G72CG82G80G69G76G81G72G71CALCG76G88G80AG81G87AG74G82G81G76G86G87，A1G17G86G88G69G88G81G76G87CALCG76G88G80AG81G87AG74G82G81G76G86G87，G76G81G87G85ACG72LLG88LAG85IPA2G85G72CG72G83G87G82G85CALCG76G88G80AG81G87AG74G82G81G76G86G87AG81G71G86G75G82G90G72G71G87G75G72G85AG83G72G88G87G76CG72G73G73G72CG87G17。CG82G81CLG88G86G76G82G81G36G88G87G75G82G85G86G86G88G74G74G72G86G87G73G88G85G87G75G72G85G76G81G89G72G86G87G76G74AG87G76G82G81G82G73G87G75G72G75AG85G80G73G88LG72G73G73G72CG87G86G82G73CG72LLG88LAG85CALCG76G88G80G82G89G72G85LG82AG71G17AG81G71G87G75G72G71G72G86G76G74G81G82G73G81G72G90CALCG76G88G80AG81G87AG74G82G81G76G86G87G86G86G75G82G88G71G69G72G73G88G85G87G88G85G72CAG85G85G76G72G71G82G88G87G76G81CG75G76G81A。G46G72G92G90G82G85G71G86G29CALCG76G88G80G82G89G72G85LG82AG71G39G76G86G72AG86G72G86CALCG76G88G80AG81G87AG74G82G81G76G86G87G86G49G72G90G87G92G83G72钙在G10995G2641G8975G2172G1025G7509G1038G18337要，我国G3822G8437G14841G1871G16855G7609结果G7186G12046我国G4633G8677人G3355G8611G3837钙G6897G1849G18339G1177在G23G19G19G80G74G5050G2503，G2494及G1025国G14841G1871学会G6524G14628G18339的G24G19G8。G3252G8504应G16825G15929钙，G17837G5062G6116G1861G16794，应G16825G16840G7171G980G3835G17926G8505。G13792G1182G3926G1321G12197学G15929钙G2460受G2052关G8892，G1075应进行G9157G1849G6518G16764，G1209G8726G7368G3921G3332G17908G12131人G13688。G2490G980方G19766，我国对细胞钙超载对人体的危害，和新型阻断剂G10301应用和研发，G4590G7422G5353G17227G17287G3827G18337G16282，G7424文对G8504作G980G12628述。G20G714钙超载G17细胞內钙超载G994G3822G12193疾病和病G10714G17819G12255的发G10995发G4649G4506G2011有关。对机体G17227作用的主要G7171钙离子（CAA1A0），但细胞内CAA1A0G7509微，G1177G1038胞外的2万分之G980，G15G3252G1038细胞的脂质双层膜形G6116屏障，G15限制水和离子的进G1849。CAA1A0主要通G17819嵌在膜上的，有孔道的特G12193蛋白质进G1849胞內，G17837G12193蛋白质就G7171CAA1A0通道，它的开关受膜电压、受体和胞内钙G18339G16855控。G17进G1849胞内的CAA1A0，由网上CAA1A0G36TP酶将CAA1A0泵G1849內质网和肌浆网G1025贮存，需要时受网上肌醇三磷酸IPA2受体和雷诺丁G85G92AG81G82G71G76G81G72受体G16855控释放至胞浆内。胞內CAA1A0G17819G3822可通G17819细胞膜上CAA1A0G36TP酶泵出胞外，或经G49AA0G16CAA1A0交換出胞外，通G17819G1209上机制维持胞内CAA1A0在低浓度下的G2172态平衡。细胞启G2172G10995G10714G8975G2172时的CAA1A0G1038G20G19A4A5G80G82L/L，持续超G17819G8504浓度即形G6116钙超载。现巳知电压依赖性钙通道分L、G49、P、Q、G53、TG18616型，分佈于不同细胞。钙通道G2460G7171由A6、2、G1861G24G12193亚基肽链合G6116，其G1025A6最G18337要，由它组G6116通水和离子的孔道。和A1A1和由二硫鍵相连G6116二聚体G1861同G17227作用G17227辅助和G16855节A6的功能。有些药G10301作用于钙通道的出G1849口的结合位点，可阻断CAA1A0进G1849细胞，防止钙超载。G1075可用药G10301抑制胞内钙库的受体，减少贮CAA1A0外释，G1209降低胞内CAA1A0A8減轻钙超载。A8A9A6A3A72G714钙超载对机体的危害及新型钙阻断剂的作用21血管平滑肌细胞钙超载和高血压G10995G10714情况下，CAA1A0使血管平滑肌细胞産G10995兴奋收缩偶联，保持其正常舒缩功能。G13792外周G4579G2172G14045平滑肌细胞钙超载时，G5353G17227持续收缩，导致血管阻G2159增高，G7171高血压发G10995的G1861同通G17347。钙阻断剂至G1182G1185G15999G6524G14628G1038G20330G17885药G10301之G980。A9A1A3A2A7血管平滑肌细胞上主要G7171L及T型钙通道。近G7481发现G1268G13491的L型钙阻断剂G81G76G73G72G71G76G83G76G81G72、G81G76CAG85G71G76G83G72等能舒G5364G13970G1849G10711G4579G2172G14045但对出G10711G4579G2172G14045G7092作用，G6937对G13970性高血压G7092效。G13792G12544G22G1207新钙阻断剂G80AG81G76G71G76G83G76G81G72、G81G76G89AG71G76G83G76G81G72、G69G72G81G93G76G81G71AG80G76G81G72和G72G73G82G81G76G83G76G81G72能同时作用L及T钙通道，G6937对G13970出G10711G4579G2172G14045G1075能舒G5385，对G13970性高血压G1075有效，G1018G17227保G6264G13970G14051作用。A9A10A3A11A7近G2460发现血管平滑肌细胞上G17836有P型钙通道，G6937T及P型钙通道阻断剂的研发和应用G7097G11422受G2052G18337G16282。最近发现高血压时，L型钙通道主要组G6116A6C亚基G15932G17810增加，钙通道G6980G18339增G3822，G1186G13792加G17907高血压的发G4649。能使A6C亚基G15932G17810G5686G3809正常的药G10301有G7407用于G1032G5214治疗。A9A6A3A5A722神经细胞钙超载G994神经元损伤G10995G10714情况下，神经细胞内CAA1A0能维持神经元的兴奋性，但G14053G5190及G11394层特G8542G2318神经元发G10995钙超载时，兴奋G19420G1552降低，能G16837发偏头痛或癫痫有人G6564出G1016G13785G3355G1038神经元兴奋性G6925G2476，G3800G1861病G10378态CG82G80G82G85G69G76G71CG82G81G71G76G87G76G82G81。巳知神经细胞上主要G7171G49、P、Q型钙通道，有G6265道钙通道A1亚基的G6982G19512，导致癫痫和G1861G8994G3845G16855。G4490G7075性偏G11263型偏头痛G5751G13785，P/Q/型CAA1A0通道亚基有G3805G5334G15G13792作用于钙通道A1亚基的药G10301G74AG69AG83G72G81G87G76G81G2842G2709G2529G2357G5064G20333G4462G2460G12228G81G72G88G85G82G87G76G81，能阻断外钙內G8981G1186G13792对癫痫和偏头痛G17227防治作用。G8504外G17836发现钙通道A1亚基G15932G17810G6925G2476的G4579G21748有痛G16285超G6947，G19820内G8892G4568A11G80G53G49G36G2465G1053G4533G7692G14539酸可抑制A1亚基G15932G17810增G3822，可减少G3252G11152痛G13792G5353G17227的行G1038。G74AG69AG83G72G81G87G76G81G1075能减轻慢性神经性G11152痛。A9A12A7G5062知G37G72G87AG9108G12893G7691蛋白损伤G14053神经元，G7171G13781G5192性G11208G2586G2460G12228阿尔茨海默病G36LG93G75G72G76G80G72G85G255G86G71G76G86G72AG86G72G96发病G2419G3252之G980，G4466G20576G15932G7138将G16825蛋白作用于神经细胞，可G5353G17227胞內钙超G17629和神经元损伤，G1032G5214应用钙阻断剂治疗取得G980G4462疗效。A9A13A723胰腺腺胞钙超载G994胰腺炎G10995G10714情况下CAA1A0作用于胰腺腺胞G20042G12483肌G2172蛋白微G1009，行使分G8864胰酶的胞G6502作用。钙超载时腺胞细胞受损G10990至G3363G8527发G10995胰腺炎，G2666G2869G3252能抑制胞内钙库的IPA2受体，减少钙库G1025CAA1A0释放G2052胞质内，减轻钙超载，G1186G13792对胰腺炎G17227效。人G13688G16855G7609结果G15932G7138G2666G2869的G9052G17165增加，使G18214G12946性胰腺炎减少，G1075G7171G1316G16789。A16但G3252G1038G2666G2869G3252对IPA2受体的G1158和G2159G17751低，G6937作用有限，正开发效果G7368G3921的G12879G1296G10301。巳发现2G16G8700基G16G1069G8699基G16G14531基G11856酸G11428（2G16AG80G76G81G82G16G72G87G75G82G91G92G71G76G83G81G92LG69G82G81AG87G72）G7171IPA2受体阻断剂，G2460能抑制钙贮存控制通道，减轻钙超G17629，应G7171G10714G5831的药G10301。可G5808有G2115作用，正G1116G1209G6925G17908，G1209减少G2115作用。A17A9A14A724G994细胞凋亡的关系G29细胞凋亡G17819度或凋亡不G17287能G5353G17227诸G3822疾病，G3926凋亡G17819度G994心肌缺血/再灌损伤、心肌梗G8527、G1025风、神经元退行性疾病、G17908血衰竭性疾病、肝胰疾病等有关，凋亡不G17287G994肿瘤、自G4490免疫病等有关，G3252G13792G16855控凋亡的药G10301G1075G5353G17227关G8892。钙离子在细胞内超载在凋亡发G10995G1025自始至终G17227作用，纠正细胞内钙离子G1207谢紊乱可减轻钙超载，能抑制细胞凋亡，G1186G13792对G3822G12193常见病、难治病G17227防治作用。在G3822G12193G4466G20576性细胞凋亡发G10995G17819G12255G1025，钙离子往往升高，并使钙蛋白酶（CALG83AG76G81）、CAA1A0/G48G74A1A0依赖性内G2011酶、钙依赖性的组织型谷G8700酰胺转移酶（G87G76G86G86G88G72G87G92G83G72G87G85AG81G86G74LG88G87AG80G76G81AG86G72）激G8975，分别G5353G17227染色体松弛，G39G49G36暴露且G15999G2011断，导致细胞凋亡。钙阻断剂可抑制上述酶的激G8975，G1186G13792G17227抗凋亡作用。凋亡信号通G17819内质网的IPA2受体释放钙离子，G17837些钙离子能迅G17907移至邻近的线粒体，促使通透性转换孔（PTP）开放，使细胞色素C及凋亡蛋白酶激G8975G3252子G36G83AG73释出，G5353发级联G2465应，激G8975CAG86G83AG86G729（半胱G3837冬蛋白酶，有G20G23G12193编号G20G16G20G23），再激G8975CAG86G83AG86G72G22，G1186G13792分解蛋白，致细胞凋亡。G13792且CAG86G83AG86G72G22微软用户G20G1075能作用于IPA2受体，形G6116正G2465馈，放G3835促凋亡作用。G3252G8504阻断内质网IPA2受体的药G10301有抗凋亡作用。A9A6A15A8A6A6A7CAG86G83AG86G72G202位于内质网的胞浆侧，不在G19766向线粒体的G980侧，G6937G7481自线粒体途径G1025的刺激不能使之激G8975。但当内质网受G2052胁迫（G86G87G85G72G86G86）或内质网钙库G15999G2172员时可使之G8975化，G8504外CACG83AG76G81G1075可G8975化CAG86G83AG86G72G202，G1016G13785G1861同形G6116“钙离子感受器”，感受CAA1A0的增高G13792G5353发细胞凋亡。G6937G13792G2011断蛋白酶之间联系和阻断內质网IPA2受体有抗凋亡作用。细胞质膜钙离子G36TP酶（PG48CG36），利用G36TP的能G18339将钙离子G6502出细胞外，G980旦PG48CG36受损钙离子G6502出受阻，G1075可致钙超载G5353G17227细胞凋亡。钙G16855蛋白能促PG48CG36G6502钙G6937有抗凋亡作用A9。G17837G7171G2490G980G12879减轻胞内钙超载G17227抗凋亡的途径。G1032G5214上G5062应用钙阻断剂抑制凋亡治疗G980些常见病和难治病，取得G980G4462疗效。例G3926能缩G4579G14053梗G8527体积和减轻迟发性神经元损伤，减轻心肌梗G8527后心肌细胞的损伤等。有良G3921的前景。G1209上G1177G1038近期文献的例举，作G13785認G1038国人对钙超载的危害及防治G1075应作G9157G1849研究。G5353G17227钙超载的各环节，可作G1038药G10301作用靶点，G1186G13792进行新型钙阻断剂的研发，会G1038分子治疗学增添新的亮点，目前有关的研究巳见陸续G6265道，盼能G5353G17227G7368G3822的关G8892。A9A6A2A7可喜的G7171现己发现有些G1025药G1075有钙阻断作用，A9A6A10A7拓宽了研发思G17347。相信基础、应用和G1032G5214研究的G4506G2011结合，G4462能G1038我国药学可持续发G4649作出新的贡献。参考文献A18A19A20A21A22A23A24A25A26A27A28A29A30A31A32A26A33A34A23A35A28A36A37A38A29A39A40A37A41A28A42A38A29A30A43A37A44A44A23A45A23A29A36A36A46A41A23A39A28A29A43A39A22A47A22A29A37A36A39A38A44A48A28A35A48A37A22A42A48A40A28A29A29A23A35A39A28A29A43A28A29A36A37A40A46A41A23A45A36A23A29A39A37A49A23A43A45A22A30A39A18A50A20A33A51A40A37A29A52A40A28A42A28A45A48A38A35A53A22A35A35A26A54A55A55A56A26A54A57A58A59A60A57A54A19A61A57A54A57A62A63A64A65A66A67A68A33A69A70A71A72A73A74A75A76A77A78A79A80A81A82A83A84A85A86A87A88A18A50A20A89A90A84A91A92A70A93A54A55A55A56A26A54A57A58A59A60A57A54A19A61A57A54A57A18A54A20A94A28A29A95A26A27A28A29A30A31A32A26A96A37A39A48A22A39A39A37A38A29A38A29A51A40A37A29A23A39A23A26A97A42A23A45A37A48A28A29A28A29A43A98A22A45A38A41A23A28A29A30A22A37A43A23A35A37A29A23A39A44A38A45A36A40A23A42A23A43A37A48A37A29A23A39A37A29A36A40A23A36A45A23A28A36A42A23A29A36A38A44A40A46A41A23A45A36A23A29A39A37A38A29A18A50A20A33A51A40A37A29A52A40A28A45A42A28A48A38A35A53A22A35A35A26A54A55A55A99A26A54A54A58A19A60A19A57A61A19A100A101A102A65A66A67A68A33A103A104A89A90A65A105A90A106A107A108A81A82A83A109A110A111A112A89A113A87A84A85A110A114A89A86A115A116A18A50A20A89A90A84A91A92A70A117A26A54A55A55A99A26A54A54A58A19A60A118A19A57A61A19A100A18A119A20A34A38A39A23A29A43A38A45A44A44A51A26A53A35A28A48A120A121A34A26A51A28A29A29A38A29A51A52A23A36A28A35A33A122A45A23A28A36A42A23A29A36A38A44A40A46A41A23A45A36A23A29A36A37A38A29A37A29A36A40A23A41A45A23A49A23A29A36A37A38A29A28A29A43A42A28A29A28A30A23A42A23A29A36A38A44A37A39A48A40A23A42A37A48A40A23A28A45A36A43A37A39A23A28A39A23A18A50A20A51A37A45A48A22A35A28A36A37A38A29A54A55A55A123A26A19A19A59A58A54A19A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