Kv7KCNQ钾离子通道开放剂研究进展-USB迷|专注于互联网分享

2024年3月6日发(作者：星勇军)

中国细胞生物学学报 Chinese Journal of Cell Biology 2015, 37(8): 1168–1172DOI: 10.11844/cjcb.2015.08.0023Kv7/KCNQ钾离子通道开放剂研究进展张凡祁金龙刘雅妮黄东阳李黎张海林*(河北医科大学药理学教研室, 石家庄 050017)摘要电压门控型Kv7/KCNQ钾离子通道广泛存在于神经系统, 在调节神经兴奋性中发挥着重要的作用。Kv7/KCNQ通道开放剂成为临床治疗神经过度兴奋相关疾病癫痫和疼痛的一种新的策略。目前, 已报道的Kv7/KCNQ通道开放剂有近30种。该文将对开放剂作用特点、作用位报点及其临床应用前景进行总结。关键词 Kv7通道; KCNQ通道; 开放剂; 癫痫; 疼痛Advance in Kv7/KCNQ Potassium Channel Openers

学 Zhang Fan, Qi Jinlong, Liu Yani, Huang Dongyang, Li Li, Zhang Hailin*(Department of Pharmcology, Hebei Medical University, Shijiazhuang 050017, China学)Abstract The voltage-gated Kv7/KCNQ potassium channels are found to be expressed wildly in the central

nervous system and play a pivotal role in controlling neuronal excitability. Kv7/KCNQ channel opener become a

new tool for clinical intervention of membrane excitability related disorders, such as seizure and pain. Currently

nearly thirty kinds of kv7/KCNQ channel openers have been reported. In this paper, we summarized the activation

物characteristics, activation sites and clinical application of Kv7/KCNQ channel ds Kv7 channel; KCNQ channel; opener; seizure; pain

电压门控型钾离子通道Kv7家族由KCNQ生胞基因Kv7.4、Kv7.5五个亚型[3]。Kv7.1通道主要表达于编码。Kv7/KCNQ电压门控钾通道在控制细胞兴奋心肌组织上, 并与KCNE通道共同编码组成延迟性中发挥着重要作用[1]。针对Kv7钾通道调节剂的整流钾离子通道(slowly activated delayed rectiﬁer

研究, 为治疗神经过度兴奋相关疾病(如癫痫、疼痛)potassium current, IKs)。IKs通道电流在心肌动作电的新药研发提供了广阔的空间。此外细, 开放剂作用位去极化过程中发挥着重要作用[4]。Kv7.1通道功能机制及结合位点的研究对离子通道功能特点的认识缺失型突变体被证实可引起遗传性1型QT间期延长也具有十分重要的意义[2]。本文将对目前已发现的综合征(long QT syndrome1, LQT1), 另有突变体引起Kv7/KCNQ钾离子通道开放剂作用特点、开放剂作Jervell Lange-Nielsen综合征(JLNS), 即伴有神经性用位点及其临床应用前景进行总结和讨论。耳聋的先天性长QT间期综合征[5]。大量研究表明, Kv7.2、Kv7.3和Kv7.5通道蛋白1 Kv7/KCNQ国通道生理病理意义以四聚体形式共表达, 所产生的电流是M电流的分Kv7中通道家族已克隆出Kv7.1、Kv7.2、Kv7.3、子基础[6]。Kv7.2及Kv7.3通道主要分布在脑部, 包括收稿日期: 2015-01-14 接受日期: 2015-05-05国家自然科学基金(批准号: 31401199)、河北省自然科学基金(批准号: H2015206427)、河北省教育厅优秀青年基金(批准号: YQ2014030)和中国博士后科学基金第56批面上资助(批准号: 2014M560194)资助的课题*通讯作者。Tel**************,E-mail:******************Received: January 14, 2015 Accepted: May 5, 2015This work was supported by the National Natural Science Foundation of China (Grant No.31401199), the Natrual Science Foundation of Hebei Province (Grant

No.H2015206427), the Outstanding Youth Foundation of Education Department of Hebei Province (Grant 2014030) and the 56th Postdoctoral Science

Foundation of China (Grant No.2014M560194)*:+86-311-86265562,E-mail:******************网络出版时间: 2015-08-19 16:40:10　　　URL: /kcms/detail/

张凡等: Kv7/KCNQ钾离子通道开放剂研究进展1169与癫痫发作密切相关的部位, 如皮层、海马、丘脑NH6相对甲氯灭酸和双氯芬酸选择性较强, 对Kv7.1区以及疼痛传导通路中的脊髓背根神经节感觉神经和Kv7.1/KCNE1通道没有作用[20]。化合物NH29选元、脊髓背角神经细胞和三叉神经元等[7-8]。Kv7.2择性更强, 对Kv7.1、Kv7.1/KCNE1和Kv7.3通道没和Kv7.3通道基因突变或M通道功能失调, 则可引发有作用, 对Kv7.4通道作用极微弱。有趣的是, NH29良性家族性新生儿惊厥症(benign familial neonatal

对TPRV1通道具有抑制作用, 有利于疼痛等相关疾seizures, BFNS)[9]。Kv7.2基因敲除的小鼠表现为病的治疗[21]。普遍的癫痫和学习记忆障碍等。此外, Kv7/M通道丙烯酰胺类化合物(acrylamides), 如Acrylamides

在许多疼痛模型中发挥重要作用, 如慢性神经性疼(S)-1和Acrylamides(S)-2,

报也被报道能激活Kv7通道。痛、炎性疼痛和癌骨转移疼痛等[10]。Kv7.2基因突(S)-1开放变还可引发外周神经超兴奋性疾病(peripheral nerve

hyperexcitability, PNH), 即肌纤维抽搐和神经性肌强直, 临床特点表现为自发和持续的肌肉组织过度兴学Kv7.2-Kv7.5通道, 同时抑制Kv7.1通道。与其他开放剂不同, (S)-1对Kv7.2和Kv7.2/Kv7.3通道的作用具有电压依赖性, 在高电压情况下抑制通奋、肌束震颤、痛性痉挛等[11]。还有研究发现, 在杏仁核兴奋引发焦虑的大鼠模型中, Kv7通道功能上调可以降低神经元过度兴奋, 有效地缓解焦虑症状[12]。学道的活性而在低电压情况下增强通道的活性。 (S)-1对Kv7.4和Kv7.5的作用则是在所有电压情况下都具有增强通道活性的作用[22]。(S)-2的EC50为0.06

μmol/L,

效价比(S)-1强约55倍[23]。

Kv7.4主要表达于内耳的耳蜗和前庭器官以及中枢听觉传导通路。已证实Kv7.4基因突变可引发遗传性耳聋症(deafness nonsyndromic autosomal

dominant 2, DFNA2)[13]。近期有研究发现物BMS204352是早期发现的Kv7通道激动剂, 2-羟基吲哚(oxindole)类似物。该化合物同时也是BK通道激动剂, 对GABA通道有微弱的抑制作用[24]。BMS204352同样开放Kv7.2-Kv7.5通道, 选择性增大生, Kv7.4在Kv7.5通道电流6倍, 但其强烈抑制Kv7.1通道, 抑制骨骼肌、内脏和血管平滑肌中均有表达[14]; Kv7.5除率为96%[25]。有趣的是, BMS204352的右旋异构体了表达于脑部, 在血管平滑肌中也有分布[15]。激活对Kv7家族通道具有抑制作用, 抑制率约为95%[12]。Kv7.4和Kv7.5通道可降低血管张力, Kv7通道已成为吡硫锌(ZnPy)是Kv7通道的强效开放剂, 该抗高血压药物新的潜在作用靶点[16]。化合物具有分子结构简单的特点。ZnPy能够激活Kv7.2-Kv7.5通道, 但对Kv7.3通道无作用[26]。虽然2 Kv7通道开放剂ZnPy能增大Kv7.1通道电流, 但对Kv7.1和KCNE1亚目前已发现的Kv7/M通道开放剂有近胞30种(表基形成的IKs电流无作用[27]。1), 对神经元Kv7通道的作用主要包括使通道激活ZTZ系列共报道了10个化合物, 构效关系的的电压依赖性向超极化方向改变、减慢通道激活研究提示氯和溴取代基为该系列化合物的必需取和去活时间常数以及增大电流幅度。其中细, 第一个代基, 如果氯和溴取代基缺失将降低其开放Kv7通被发现同时研究最深入的一个道活性[28]。以先导化合物ZTZ240为例, 最显著的特滨(retigabine; D-23129)国Kv7通道开放剂是瑞替加。Retigabine能够激活点为增大Kv7.2通道的去活时间常数可达数百倍[28]。Kv7.2-Kv7.5通道, 对Kv7.1通道具有微弱的抑制作ZTZ233又名ICA27243, 化合物ICA27243是美国用。Retigabine对Kv7通道家族选择性强弱顺序为Icagen公司研发的Kv7通道开放剂, 具有高选择性Kv7.3>Kv7.2/Kv7.3>Kv7.2>Kv7.4中[17]。和效价较高的特点。ICA27243对Kv7.2/Kv7.3通道灭酸酯类(fenamate)是一大类重要的Kv7通道选择性作用高于Kv7.4和Kv7.3/Kv7.5通道[29]。激活剂, 代表化合物包括甲氯灭酸(meclofenamic

吡唑并咪唑嗪类化合物是本实验室合成及报acid)、双氯芬酸(diclofenac)[18]以及在两者基础上道的一系列具有开放Kv7通道作用的化合物。采结构改造合成的芬那酯类衍生物NH6和NH29等一用Rb+流出高通量筛选, 这一系列化合物构效关系系列化合物。甲氯灭酸选择性增大Kv7.2通道电流为: 母环上R取代基以三氟甲基为必需取代基, R1以作用强于Kv7.3通道。双氯芬酸选择性增大Kv7.2-苯环及萘环为最佳取代基, R2以含多个强吸电子集Kv7.4通道电流, 反而抑制Kv7.5电流[19]。化合物团为最佳取代基。QO-58为先导化合物, 选择性作

1170·综述·用于Kv7.2和Kv7.4通道, 对Kv7.3通道作用影响较(leucine)残基。研究发现, 当Trp-236位点突变为亮微弱。另外, QO-58作用类似ZTZ240能够显著延长氨酸残基时, Kv7.2-Kv7.5通道就不再被retigabine所Kv7.2通道去活常数近10倍[30]。本实验室还发现, 非增强。相反, 当Kv7.1通道相应的亮氨酸残基突变甾体抗炎药塞来昔布(celecoxib)也具有激活Kv7.2-为色氨酸残基时, 突变的Kv7.1通道变为对retigabineKv7.5通道的作用。不同的是, 塞来昔布对Kv7.1通敏感。可见, 保守的色氨酸明显是retigabine介导的道具有抑制作用, 最大抑制率为60%[31]。强化作用所必需的[32]。有趣的是, Trp-236位点也是很多其他Kv7通道开放剂的作用位点, 如BMS-3 Kv7通道开放剂作用位点204352、Acrylamides(S)-1报、Acrylamides(S)-2、Kv7通道开放剂增加通道电流的机制主要包括ZTZ240和塞来昔布[22,31,33-34]。这表明, 这几类化合物降低通道激活阈值、增加通道开放频率及稳定通道可能以相似的方式作用于的开放构象等。开放剂与通道结合时引发多种效应,

促进一系列构象改变以打开通道。当离子通道某些学Kv7通道并需要相同的分子基础。氨基酸残基发生改变时, 这些开放剂的活性消失或者下降, 这些氨基酸残基位点被我们称为作用位点。影响开放剂作用的通道残基可能是改变了开放剂与通道作用的亲和力或阻碍了开放剂诱导的构象改学基于对Kv7.2通道的单定点突变研究, ZnPy的分子作用位点也已有报道, 分别是S5区的亮氨酸残基(Leu249)、位于S5区和孔区之间连接肽段上的亮氨酸残基(Leu275)和S6片段上的丙氨酸残基(Ala306)。变。这些小分子化合物作用机制的研究对于我们了解Kv7通道功能特点具有重要意义。Retigabine激活Kv7通道的作用与Kv7.2-Kv7.5通道第五次跨膜(S5)上的一个保守的色氨酸残基物对亮氨酸残基Leu249和Leu275进行双突变, 虽然ZnPy并不引起IV曲线改变, 但仍能导致通道总电导的提高。相反地, 对S6片段上的Ala306进行突变, 只引起很小的ZnPy诱导的通道总电导提高, 但仍可导致IV曲线超极化方向变化。因此, 这三个位点代表有关, 在相应的Kv7.1通道上其对应位置是亮氨酸生了ZnPy作用的两种不同的关键调控位点[35]。表1 Kv7通道开放剂化合物名称靶基因胞Table 1 Summary of Kv7 channel activators半数有效浓度(μmol/L)作用位点Compound nameTarget genes EC50 (μmol/L)Acting sitesAcrylamides (S)-1[22]Activate Kv7.2, Kv7.3, Kv7.4, Kv7.5 and Kv7.2/ 3.28Trp236Kv7.3; Inhibit Kv7.1Acrylamides (S)-2[23,34]Activate Kv7.2细 0.06Trp236BMS-204352[24]Activate Kv7.5>Kv7.4>Kv7.2, K7.3, Kv7.2/ –Trp236Kv7.3; Inhibit Kv7.1Celecoxib[31]Activate Kv7.2, Kv7.3, Kv7.4, Kv7.5 and Kv7.2/ 4.9Trp236Kv7.3; Slightly inhibit Kv7.1Diclofenac[18-19] 2.6–Meclofenamic acid[18] 11.7–NH6[20] 18–NH29[21]国Activate Kv7.2, Kv7.3, Kv7.4 and Kv7.2/Kv7.3;

Inhibit Kv7.5Activate Kv7.2, Kv7.3 and Kv7.2/Kv7.3Activate Kv7.2/Kv7.3Activate Kv7.2; Inhibit TPRV1 14Arg198 and Arg207 in the voltage

sensing domain (VSD)Retigabine[17,32] 0.34Trp236QO-58[30] 2.3Ala306, Leu275 and

Val224Val225Tyr226ZTZ240[28]中Activate Kv7.3>Kv7.2/Kv7.3>Kv7.2>Kv7.4, slightly

inhibit Kv7.1Activate Kv7.1, Kv7.2, Kv7.4 and Kv7.2/Kv7.3Activate Kv7.2, Kv7.4 and Kv7.5 9.8Trp236 and Ala309ICA27243[29]Activate Kv7.2/Kv7.3>Kv7.4>Kv7.3/Kv7.5 0.4–Zinc pyrithione[26-27]Kv7.1, Kv7.2, Kv7.4, Kv7.5 and Kv7.2/Kv7.3 1.7Leu249, Leu275 and Ala306–: 无相关文献。–: no related paper.

张凡等: Kv7/KCNQ钾离子通道开放剂研究进展1171ZTZ240作用位点包括S5上的色氨酸残基关疾病的治疗具有广阔的应用范围和不可低估的应(W236)和S6上的丙氨酸残基(A309)。ZTZ240引起用价值。Kv7.2W236L突变体通道IV曲线左移程度降低。将A309丙氨酸残基突变为半胱氨酸、结氨酸和甘氨酸,

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