2017, Vol. 52
2. 青岛大学药学院, 山东 青岛 266021
2. School of Pharmacy, Qingdao University, Qingdao 266021, China
瞬时受体电位 (transient receptor potential, TRP) 通道是存在于细胞膜上的非选择性阳离子通透的离子通道。迄今在哺乳动物中, 超家族TRP通道有28个成员[1]。根据其氨基酸序列的同源性差异, TRP通道家族可分为7个亚族, 分别为TRPA (ankyrin)、TRPC (canonical)、TRPM (melastatin)、TRPML (mucolipin)、TRPN (NOMPC)、TRPP (polycystin) 和TRPV (vanilloid)[2]。TRP离子通道在哺乳动物体内分布较为广泛, 与感觉信息传递 (如视觉、痛觉和温度觉等)、调节细胞内Ca2+平衡及生长发育等生理活动密切相关。TRP通道基因突变导致多种系统疾病的发生, 如TRPC6有6种基因突变都与局灶性节段性肾小球硬化症的发生有关; TRPM1有14种基因突变与先天性的夜盲症相关; TRPM2和TRPM7的基因突变与肌萎缩性脊髓侧索硬化症相关; TRPM6的基因突变与低镁继发性低钙血症相关; TRPML1的基因突变与Ⅳ型粘多糖症相关; TRPP2的基因突变与多囊性肾病相关[3]; TRPA1的基因突变与一种家族偶发性的疼痛综合症有关; TRPV3的基因突变与奥姆斯特德综合症 (Olmsted syndrome) 有关; TRPV4的基因突变与人脊椎干骺端发育不良、肩腓肌脊髓性肌萎缩、2C型腓骨肌萎缩症和末梢神经痛相关[4]。因此, 了解TRP离子通道的生物学特征及已发现的天然调节剂的作用机制, 对发现更为有效、特异的天然药物分子用于治疗疾病和提高人类健康水平具有重要的意义。
纵观TRP通道及其调节剂的研发历程不难看出, 天然活性产物作为工具在TRP通道的发现方面发挥了重要作用。一些具有芳香、辛辣及刺激性的天然小分子化合物, 如辣椒素、薄荷醇、大蒜素、胡椒碱和姜黄素等已被证实是TRP通道的重要调节剂, 特别是辣椒素的发现, 极大推动了TRPV1通道蛋白的功能研究及其他同源通道蛋白的发现。近年来, 解析的TRPV1通道蛋白结构显示其为四聚体 (图 1a), 通道孔区位于4个对称亚基形成的结构正中, 决定离子的选择性和转运速度。当离子和小分子化合物进入孔区时, 能影响离子流的方向。辣椒素结合并激动TRPV1时, 高门几乎没有结构的变化, 而是由低门打开产生离子流 (图 1b)[5, 6]。但是, 植物或动物毒素如RTX或DkTx激活TRPV1时, 高门和低门都发生了极大的结构变化。目前, 辣椒素作为治疗带状疱疹后的神经病理痛的药物研发已进入Ⅲ期临床试验[7]。
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Figure 1 The cryo-electron microscopy structure and dual-gate diagram of rTRPV1[5, 6]. a: Bottom view focusing on trans membrane core, including S1-S4 and S5-P-S6 pore modules. b: Solvent-accessible pathway along the pore mapped using the HOLE program for capsaicin-bound TRPV1 structure. There is no change in the selectivity filter that was named after upper gate, whereas the lower gate is markedly expanded |
鉴于天然产物在TRP通道调控方面发挥的重要作用, 本文试图综述TRP通道天然调节剂的研究进展, 并归纳总结不同类型的天然产物对TRP通道各亚型的选择性及作用强度, 旨在为更多天然调节剂的发现及创新药物研究提供参考与指导。
1 TRPV通道哺乳动物的TRPV亚族包含6个成员, TRPV1~6。TRPV1~4通道为非选择性阳离子通道, 在感觉神经元中表达, 对温度、渗透压及机械力的变化较为敏感, 可传递热、痛等外界刺激信号; TRPV5和TRPV6则对Ca2+有较高的选择性, 对温度的敏感性较低, 与TRPV1~4的同源性较低[8]。
1.1 TRPV1TRPV1通道又称为辣椒素受体, 辣椒素等化学成分、pH < 6、温度 > 42 ℃及P物质 (substance P, SP) 等均可激活该通道, 引起阳离子如Ca2+内流、K+外流, 从而导致SP和降钙素基因相关肽 (calcitonin gene-related peptide, CGRP) 的释放, 引起伤害性疼痛感受[9]。包括天然产物在内的许多TRPV1通道调节剂已被证明对多种动物模型的疼痛有效缓解作用, TRPV1已成为开发镇痛药物的重要靶标[10]。
1.1.1 辣椒素及其类似物辣椒素 (capsaicin), 又名辣椒碱, 为茄科辣椒属植物红辣椒 (Capsicum annuum) 的活性成分, 有镇痛抗炎、促进食欲和抗菌杀虫等作用[11]。辣椒素可选择性激活TRPV1通道, 引发持续的Ca2+内流, 该作用可被TRPV1的竞争性拮抗剂辣椒平 (capsazepine) 阻断。辣椒素可使TRPV1受体处于脱敏状态或使神经末梢退化, 从而缓解疼痛[12]。TRPV1的脱敏与依赖于PKA (protein kinase A), PKC (protein kinase C), CaMKII (Ca2+/ calmodulin-dependent protein kinase Ⅱ) 的磷酸化作用、磷酸酶催化的去磷酸化作用、PIP2 (phosphate dylinosital biphosphate), ATP (adenosine triphosphate) 及糖基化作用等因素相关[13-15]。运用分子生物学和电生理手段确定, Y511和S512位 (大鼠源TRPV1氨基酸序列) 是影响辣椒素与TRPV1通道结合的重要位点[16]。近期也有研究认为, T551和Y571 (小鼠源TRPV1氨基酸序列) 两个位点对辣椒素与TRPV1的结合影响较大[17]。Elokely等[18]通过电子云密度图的分析和功能学实验更精确地呈现了辣椒素与TRPV1结合的模式, Y511、E570和I569形成的亚结合口袋较深, 可容纳辣椒素, 功能学实验表明L515、L553、Y554、I573和F587也是辣椒素结合口袋的重要组成。
胡椒碱 (piperine) 和丁香子酚 (eugenol) 与辣椒素结构相近, 具有相似的属性及作用。胡椒碱对人源TRPV1有强效的激活作用, 最大效应为辣椒素的2倍, 该作用可被辣椒平及TRPV1的非竞争性拮抗剂钌红 (ruthenium red) 阻断。相较于辣椒素, 胡椒碱使TRPV1通道脱敏的效果更为明显[19]。
辣椒素酯 (capsiate) 属于类辣椒素类物质, 存在于甜椒中, 无辛辣味。体外研究表明, 辣椒素酯可激活表达在人胚肾 (human embryonic kidney, HEK)-293细胞中的TRPV1通道, 且与辣椒素的效力非常相似。辣椒素酯亦有减肥作用, 有研究表明辣椒素酯可增加野生型TRPV1小鼠的能量代谢, 而TRPV1基因敲除的小鼠不会有此表现[20]。在美国和日本等国家, 已有关于辣椒素酯制成的控制体重的产品在市场销售[21]。
1.1.2 植物毒素类物质树脂毒素 (resiniferatoxin, RTX) 和亭牙毒素 (tinyatoxin, TNX) 为该类物质的代表性成分, 是目前已知的、活性最强的TRPV1通道激动剂[1]。RTX存在于植物树脂大戟 (又称胶大戟, Euphorbia resinifera) 中。树脂大戟在民间常用于医治牙痛及慢性疼痛[22]。RTX通过激活TRPV1受体, 引发持续的Ca2+内流, 导致神经末梢退化并阻断痛感的传递, 从而减轻疼痛[23]。对TRPV1结构中S4上的M547进行点突变, 电生理实验表明该位点对于RTX与TRPV1的结合至关重要。在RTX的头部引入卤素原子碘, 会使改造后的RTX变成TRPV1竞争性的抑制剂碘代树脂毒素 (iodoresiniferatoxin, I-RTX)。此外, RTX还可影响体温调节、缓解神经源性炎症[24], 鞘内应用RTX可缓解持续性疼痛 (如晚期癌痛)[25]。因其与TRPV1高度的亲和性, 氚代RTX ([3H]-RTX) 常用于配体结合实验, 用于体外检测其他配体与TRPV1受体的亲和力[26]。
1.1.3 动物毒液千里达老虎尾蜘蛛 (Psalmopoeus cambridgei) 中的毒液VaTx1、VaTx2和VaTx3[27], 对TRPV1的激活能力为VaTx3 > VaTx2 > VaTx1。VaTx3对TRPV1有很强的选择性, 对TRPV2、TRPV3和TRPV4无激活作用。塔兰图拉毒蛛 (Tarantula) 中的毒液DkTx为TRPV1受体激动剂[28], DkTx和TRPV1的结合具有很高的亲和力及不可逆性, 和其他毒素相比, 洗脱1~2 min之后激活电流才会减小, 洗脱15 min后, 电流减小20%左右; DkTx激活的电流可被钌红抑制。通过构建嵌合体研究发现, DkTx主要与TM5和TM6之间的胞外区结合, 作用于外孔区, 且每个DkTx都与独立的亚基相互作用。漏斗网蜘蛛 (Agelenopsis aperta) 中的毒液agatoxin 489和agatoxin 505可抑制TRPV1受体[29]。最近有研究者从中国红头蜈蚣 (Chinese red-headed centipede) 中发现了一种新型毒素RhTx, 为27个氨基酸组成的多肽, 可强效激活TRPV1受体, 引发剧烈疼痛。RhTx在正常体温下, 通过降低TRPV1的热激活温度阈值引发通道的巨大激活效应。RhTx与TRPV1的相互作用是通过其富集电荷的C端发挥作用, 并且毒素紧密结合TRPV1的孔区螺旋 (pore helix) 和转角结构 (turret), 导致通道的激活, 不同于辣椒素激活TRPV1的途径[30]。
1.1.4 姜属植物成分生姜 (Zingiber officinale) 中存在一些可激活TRPV1及A1通道的活性成分, 如姜辣素 (6-, 8-, 10-gingerols)、姜烯酚 (6-, 8-, 10-shogoals) 及姜油酮 (zingerone)。它们与辣椒素类化合物结构相近, 均含香草基, 羟基对位被长链的脂肪酰基取代。它们在TRPV1表达的细胞中可引起内向电流及胞内Ca2+浓度升高[31]。姜油酮在生姜中含量较少, 加热后可由姜辣素转化而来; 姜烯酚由姜辣素脱水而来, 脱水后对TRPV1激活能力更强[32]。
1.1.5 吴茱萸属植物成分吴茱萸 (Evodia rutae carpa) 为常用中药, 有散寒止痛、降逆止呕之效[33]。通过45Ca2+摄取实验研究表明, 吴茱萸碱 (evodiamine) 是TRPV1的完全激动剂, 能被辣椒平抑制。在TRPV1转染的中国仓鼠卵巢 (Chinese hamster ovary, CHO) 细胞中, 吴茱萸碱可抑制[3H]-RTX与受体的结合, 还可促进细胞对Ca2+的摄取[34]。在一定剂量范围内, 给小鼠皮下注射吴茱萸碱会导致剂量依赖性的疼痛反应 (舔爪行为), 而高剂量的吴茱萸碱可使感觉神经元脱敏, 从而产生持续性的抗伤害性疼痛作用[35]。吴茱萸碱味道并不辛辣, 因而有学者认为吴茱萸碱的镇痛活性可能还与除TRPV1通道外的其他靶点有关[36]。1.1.6大麻素类成分大麻素类化合物 (cannabi noids) 是植物大麻 (Cannabis sativa) 中特有的含有烷基和单萜分子结构的一类次生代谢产物, 目前已分离鉴定出70余种[37]。大麻二酚 (cannabidiol) 是较明确的TRPV1受体激动剂, 在TRPV1表达的HEK-293细胞中, 可抑制[3H]-RTX与受体的结合, 其镇痛作用可能与TRPV1通道有关[38]。
1.1.7 人参皂苷类成分动物实验表明人参总皂苷 (ginsenosides) 可抑制由辣椒素诱发的疼痛反应。体外研究表明, 人参总皂苷可抑制背根神经节 (dorsal root ganglion, DRG) 中由辣椒素诱导的电流, 而在表达TRPV1的爪蟾蜍卵母细胞中, 人参总皂苷可增强该电流。这提示人参总皂苷对TRPV1受体有激动剂和抑制剂的双向调节作用[39]。其中, 人参皂苷Rg1为TRPV1受体阻断剂, 具有与辣椒平相似的作用。在TRPV1基因转染的细胞中, 人参皂苷Rg1可阻断由辣椒素及氢质子诱导的Ca2+内流。在角质形成细胞中, 人参皂苷Rg1可抑制由辣椒素诱导的环氧合酶-2 (COX-2) 和核转录因子NF-κB的表达, 以及前列腺素E2 (PGE2) 和白介素 (IL-8) 的释放[40], 这可能为人参皂苷Rg1发挥抗炎镇痛作用的基础。
1.1.8 香豆素类化合物植物白芷 (Angelica dahurica) 中的欧前胡素 (imperatorin) 为TRPV1通道的部分激动剂。欧前胡素激动的电流可被TRPV1的特异性抑制剂JNJ-17203212所阻断。点突变研究表明, 其激活作用与Y511A/S512A位点相关。欧前胡素能够加速TRPV1的脱敏, 并且延长TRPV1从脱敏中恢复, 从而抑制辣椒素及福尔马林诱导的伤害性疼痛反应。此外, 欧前胡素还可增强酸对TRPV1的激活作用[41]。欧前胡素作为活性先导化合物, 提示呋喃香豆素类成分可能为一类新型的TRPV通道调节剂, 具潜在的镇痛治疗效果。
本课题组从翼叶九里香 (Murraya alata) 中分离得到了一种新型香豆素muralatin L, 可选择性激活过表达于HEK-293细胞的TRVP1受体并激活DRG神经元中内源性表达的TRPV1通道。对Y511 (人源) 做定点突变确认, muralatin L与Y511形成的氢键对于该化合物和TRPV1的结合起着关键性作用。动物实验表明, muralatin L可改善由福尔马林和醋酸诱导的小鼠疼痛模型, 而对TRPV1基因敲除的小鼠模型无效[42]。
1.1.9 不饱和二醛萜烯类物质该类成分大多为结构中含有α, β-二醛官能团的萜烯类成分。目前已发现水蓼 (Polygonum hydropiper) 中的水蓼二醛 (poly godial)、绒白乳菇 (Lactarius vellereus) 中的异绒白乳菇醛 (isovelleral)、襄荷 (Zingiber mioga) 中的miogadial及miogatrial等16种天然产物可激活TRPV1通道[43-46]。
1.1.10 三异戊二烯基酚类物质该类化合具有共同的结构特点, 即3个异戊二烯基首尾相连成链状结构 (或成环), 取代 (多羟基) 苯酚上的一个氢原子。目前已知4种该类化合物可选择性作用于TRPV1通道:绵地花菌 (Albatrellus ovinus) 中的scutigeral为TRPV1受体的激动剂[47], 而地花菌 (Albatrellus confluens) 中的奇果菌素 (grifolin)、盖多孔菌提取物 (neogrifolin) 及地花菌素 (albaconol) 可阻断TRPV1受体[48]。
1.1.11 其他香草醛 (vanillin)[49]、香芹酚 (thymol)、愈创木酚 (guaiacol)、樟脑 (camphor) 及百里香酚 (carvacrol) 等都激活TRPV1通道[50], 而α-菠菜甾醇 (α-spinasterol)[51]、毒胡萝卜素 (thapsigargin)[52]及育亨宾 (yohimbine)[53]等则为TRPV1受体的阻断剂。
1.2 TRPV2TRPV2通道对温度敏感性不高, 能被高温 ( > 52 ℃) 激活。近期报道的全长TRPV2冷冻电镜结构显示, TRPV2的孔区上方和下方各有一个门, 与关闭的TRPV1通道相比, TRPV2的高门和低门更宽[54]。大麻素类化合物可以激活TRPV2通道。令人至幻成瘾的四氢大麻酚 (Δ9-tetrahydrocannabinol) 是首个被发现的TRPV2的天然激活剂, 其存在于植物中可防止植物受到病原体及食草动物的伤害, 还可有效地保护紫外线的过度辐射。其对TRPV2通道的激活作用可被钌红阻断[55]。大麻二酚和四氢次大麻酚 (tetra hydrocannabivarin) 也是较强的TRPV2受体激动剂, 大麻酚酸 (cannabinolic acid) 可激活TRPV2受体, 但活性较低[56]。最近有研究表明大麻素类化合物激活TRPV2, 促进Ca2+内流及药物的吸收, 与卡莫司汀 (carmustine) 协同发挥细胞毒作用, 诱导胶质瘤细胞凋亡[57]。
1.3 TRPV3TRPV3亚族与TRPV1的同源性较高, 在32~ 39 ℃的温度刺激中被激活, 在皮肤、舌和鼻等处高度表达[58]。许多单萜类成分为TRPV3通道激动剂, 具有环状结构和羟基的单环单萜类成分对TRPV3通道的激活能力最强[59]。薄荷脑、樟脑和柠檬醛 (citral) 等可激活TRPV3受体[60, 61], 其中, 樟脑对人源的TRPV3点突变C169S几乎没有激活作用。
丁香子酚为辣椒素近似物, 可抑制环氧合酶, 具有明显的镇痛抗炎活性。它可激活TRPV1及TRPV3通道, 在HEK-293细胞TG神经元中诱导内向电流及持续Ca2+内流, 促进白介素-1α的释放, 其抗炎镇痛作用可能与此相关[50]。
大麻二酚、四氢次大麻酚[62]、因香酚 (incensole)[63]以及其他小分子酚类物质, 如香草醛、香芹酚和百里香酚等[60]也可激活TRPV3受体。
1.4 TRPV4TRPV4通道可被细胞肿胀及舒适温度 ( > 27 ℃) 激活, 人体对机械性刺激的感受可能与TRPV4有关[64]。紫杉醇 (paclitaxel) 对癌症有确切的疗效, 其对TRPV4及A1有激活作用, 可诱发接触性及寒冷性疼痛, 促使CGRP释放, 从而引发神经病变[65], 成为紫杉醇的潜在不良反应。次大麻二酚 (cannabidivarin)、四氢次大麻酚[62]及双穿心莲内脂A (bisandrogra pholide A)[66]也可激活TRPV4通道。
2 TRPC通道TRPC通道为渗透压与机械力的生物感受器。根据结构与功能可将其分为3类: TRPC1和TRPC2为一类, TRPC3、TRPC6和TRPC7为一类, TRPC4和TRPC5为一类[67]。贯叶金丝桃素 (hyperforin) 为TRPC6通道的激动剂, 作用于中枢神经系统, 引起Ca2+内流, 诱导5-羟色胺和去肾上腺素等神经递质的释放, 从而起到抗抑郁的作用[68]。贯叶金丝桃素在TRPC6过表达的神经元中可诱导树突增长及突触形成, 具有一定的神经保护作用, 可增强学习记忆能力[69]。毒叶下珠 (Phyllanthus engleri) 中的一种氧桥愈创木烷型倍半萜englerin A是一种具有高度选择性的肾癌细胞抑制剂, 可强效激活TRPC4及与其同源性较高的TRPC5受体, 在TRPC4及C5表达的细胞中引发Ca2+内流及细胞膜去极化。Englerin A对TRPA1、V3、V4及M8通道亦有较弱的抑制作用[70]。黄酮醇类成分高良姜黄素 (galangin) 能抑制由镧系元素激活的过表达于HEK-293细胞的TRPC5通道[71]。
3 TRPP通道TRPP通道亚家族包含3个成员, TRPP1、TRPP2和TRPP3, 该通道与常染色体显性遗传性多囊肾病 (autosomal dominant polycystic kidney disease, ADPKD) 关系密切。ADPKD的主要病因是人体缺少了PKD (polycystic kidney disease)-1或PKD-2基因, 导致肾小管上皮细胞中钙信号缺失, 而PKD2基因编码TRPP2通道[72]。雷公藤内酯或雷公藤甲素 (triptolide), 一种环氧二萜内酯, 具有免疫抑制、抗炎及抗增殖作用[73]。它可与TRPP2受体结合, 促使肾小管上皮细胞内钙浓度升高, 抑制细胞增殖, 从而抑制囊肿的形成, 减轻多囊性肾病的症状[74]。
4 TRPA通道TRPA1是在TRPA亚家族中发现的唯一成员, 与感觉生理学的领域相关。TRPA1具有Ca2+通透性, 可被低温 ( < 17 ℃) 激活, 常被视为伤害性刺激的感受器[75], 在小直径的TG和DRG神经元中表达[76]。TRPA1的冷冻电镜结构显示, 它的胞内有较大的N末端和C末端, 占通道总分子量的80%, N末端具14~18个锚定蛋白重复序列, 四聚化的卷曲结构 (coiled-coil) 位于离子透过孔的下方靠近C末端。天然产物对TRPA1通道的激活机制主要有两种:一是对TRPA1氨基末端的半胱氨酸残基进行共价修饰, 该激活方式与配体跟受体之间的亲和力无关; 二是配体可与受体特定的结合位点发生结合, 从而激活受体[77]。
4.1 亲电子性调节剂该类化合物亲电性较强, 或具有一定的氧化性, 以上述第一种机制激活TRPA1通道。肉桂醛和异硫氰酸丙烯酯 (allyl isothiocyanate, AITC) 等亲电子调节剂能够激活TRPA1通道, 是由于化合物与半胱氨酸中的巯基 (亲核基团) 形成了共价键或氧化形成分子内二硫键。C415S、C422S和C622S位点突变后, 影响TRPA1通道的基本功能, 证实在AITC等化合物激活TRPA1通道的过程中, 这3个氨基酸位点起着重要的作用[78]。
肉桂醛 (cinnamaldehyde) 可激活在神经末梢中表达的TRPA1, 促进CGRP及SP等血管活性物质的释放, 有益于心血管功能[79]; 还可促进胰岛素及肠促胰岛素的释放, 从而降低血糖水平, 对Ⅱ型糖尿病的治疗有一定帮助[80]。
大蒜素 (allicin) 及二硫化二丙烯 (diallyl di sulphide) 可激活在HEK-293细胞及爪蟾蜍卵母细胞中表达的TRPA1通道, 且大蒜素激活效果更佳[81]。大蒜具有一定的抗肿瘤活性, 在民间用于治疗皮肤癌。其抗癌作用可能由于其中的活性成分激活TRPA1通道, 引起过量的Ca2+内流, 诱导癌细胞死亡[82]。
AITC存在于十字花科的多种植物中, 可激活TRPA1通道, 促使Ca2+内流及神经递质的释放, 调节由胞内Ca2+诱导的细胞功能。AITC具有一定的抗肿瘤活性, 口服生物利用度较高[83]。
藁本内酯 (ligustilide) 可选择性激活表达于CHO细胞上的TRPA1通道。随着植物生长, 藁本内酯逐渐氧化产生去氢藁本内酯 (dehydroligustilide), 该物质低浓度时抑制、高浓度时激活TRPA1通道[84]。
4.2 单萜类化合物单萜类化合物伞形酮 (umbellulone) 可与半胱氨酸残基结合, 选择性激活HEK-293细胞及大鼠三叉神经元中表达的TRPA1受体。加州月桂的气味可引发头痛, 故在民间又被称为“头疼树”, 这可能由于TRPA1受体被激活后会促进CGRP的释放, 引起脑膜血管扩张, 从而引发偏头痛[85]。
桉树 (eucalyptus) 中的桉树脑为TRPA1通道的天然调节剂。1, 4-桉树脑 (1, 4-cineole) 可激活TRPA1受体, 1, 8-桉树脑 (1, 8-cineole/eucalyptol) 则阻断TRPA1受体[86]。可见取代基的不同位置会带来活性的逆转。
龙脑 (bornel), 俗称冰片, 为TRPA1受体抑制剂。在爪蟾蜍卵母细胞及三叉神经节中, 龙脑会阻断TRPA1介导的阳离子电流, 还可抑制尼古丁对TRPA1受体的激活作用。龙脑作为一种潜在的活性物质, 有望治疗TRPA1相关的离子通道疾病, 如三叉神经痛和尼古丁戒断症状等[87]。
紫苏醛 (perillaldehyde) 和紫苏酮 (perillake tone)[88]等单萜类化合物也可激活TRPA1受体。樟脑[89]和薄荷脑[90]则低浓度时激活、高浓度时阻断TRPA1受体。由樟脑诱发的TRPV1受体脱敏及TRPA1受体的阻断可能为其镇痛作用的基础。
4.3 大麻素类成分大麻素类成分不仅对TRPV1有良好的激动作用, 对TRPA1通道也有激动作用[56, 91], 该类化合物的镇痛抗炎活性可能与这两个通道相关。其中四氢大麻酚可通过共价修饰和与结合位点结合两种方式激活TRPA1受体[92]。
4.4 茋类化合物欧洲葡萄 (Vitis vinifera) 中的两种茋类化合物 (stilbenoids), 白藜芦醇 (resveratrol) 及赤松素甲醚 (pinosylvin methyl ether) 为TRPA1通道抑制剂, 在TRPA1转染的HEK-293细胞中, 可抑制由AITC引起的内向电流。另外, 二者均可抑制TRPV1受体, 在TRPV1转染的HEK-293细胞及DRG神经元中, 抑制由辣椒素诱导的内向电流, 并可减轻由辣椒素引发的疼痛反应[93]。
4.5 鞘氨醇类物质有学者从海绵Leucetta sp.中分离得到2种鞘氨醇类物质 (leucettamol A和B), 并合成出了4种类似物。它们可双向调节TRPA1受体, 并对TRPM8受体有强效抑制作用。该类物质是目前发现的第一类可作用于TRPA1通道并抑制TRPM8通道的海洋来源的天然产物[94]。
4.6 其他姜黄素 (curcumin) 是TRPA1受体的激动剂[95], 它作用于在支气管黏膜细胞中表达的TRPA1受体, 可缓解囊性纤维化症状[96]。荷包牡丹碱 (dicentrine) 可抑制由肉桂醛诱发的急性疼痛, 而对辣椒素引发的急性疼痛无效[97]。尼古丁低浓度时激活、高浓度时抑制TRPA1受体[98]。鼠尾草酚 (carnosol) 为TRPA1受体激动剂, 具有一定的镇痛抗炎活性, TRPA1可能为其作用靶标[99]。香芹酚能激活TRPA1通道并使TRPA1迅速脱敏, 重复多次给予相同浓度的香芹酚, TRPA1的电流逐渐减小[100]。
5 TRPM通道TRPM家族共有8个成员, 为通透Ca2+及Mg2+的离子通道。TRPM6及TRPM7对Ca2+通透性较高, TRPM4及TRPM5对Ca2+的通透性较差[2]。TRPM家族许多成员具有参与细胞增殖和变异的特性, 常被视为细胞生长和死亡的调节器[101]。
5.1 TRPM2TRPM2基因高表达于大脑, 其基因突变与精神疾病如双相情感障碍相关[102]。TRPM2通道的生理作用可能与胰岛素分泌和免疫细胞对肿瘤坏死因子 (TNF-α) 的作用有关[103, 104]。最新的研究表明, TRPM2是下丘脑视前区的神经元亚群中的温度感受器, 可检测到体温上升并防止过度发热[105]。TRPM2还可能参与脑卒中的病生理学机制[106]。虽然目前尚未发现靶向TRPM2通道的天然调节剂, 但鉴于其丰富的病生理学功能, TRPM2通道作为潜在的作用靶标可能为天然活性物质的发现及新药的研发提供帮助。
5.2 TRPM3与TRPM6和TRPM7通道相似, TRPM3通道受胞内Mg2+水平的调控, 可在低渗状态下被高温及一些内源性物质激活[107]。最近有研究发现, 芒柄花酚 (ononetin)、柚皮素 (naringenin) 及橙皮素 (hesperetin) 可选择性抑制TRPM3受体, 柚皮素及橙皮素的代谢产物圣草酚 (eriodictyol) 也为TRPM3受体的抑制剂[108]。
5.3 TRPM7TRPM7为2价阳离子通道, 调节细胞内Mg2+平衡, 以维持细胞生长繁殖及生理功能[109]。奎宁 (quinine), 一种具有抗疟活性的生物碱, 是TRPM7受体的抑制剂[110]。Waixenicin A为二萜类成分, 从一种夏威夷软珊瑚Sarcothelia edmondsoni中分离得到, 选择性阻断TRPM7受体, 可有效地抑制细胞的生长和繁殖[111], 对于某些癌症具有一定治疗潜力。此外, 香芹酚也可阻断TRPM7受体[112]。
5.4 TRPM8TRPM8是一种非选择性的阳离子通道, 为低温信号的感受器, 可被低温 ( < 25 ℃) 和一些“寒凉”的化合物 (如薄荷脑等) 激活[113]。许多单萜类成分可作用于TRPM8通道, 薄荷脑是研究最为深入的TRPM8激动剂。在TRPM8表达的CHO及HEK-293细胞中, 薄荷脑可引起剂量依赖性的胞内Ca2+浓度升高[114]。其镇痛、抗炎和抗肿瘤等活性可能与此相关。其他单萜类化合物, 如伞形酮[115]等对TRPM8通道有激活作用, 紫苏醛和紫苏酮[88]等为该通道的抑制剂。
目前, 在自然界发现了5种大麻素类物质可作用于TRPM8通道:大麻二酚、大麻二酚酸、四氢大麻酚、四氢大麻酚酸及大麻萜酚均为TRPM8受体的强效抑制剂[91]。
红景天苷 (salidroside) 可抑制TRPM8受体, 减少TRPM8受体在细胞中的表达。在低温环境 (18 ℃) 下, 红景天苷能抑制人类支气管上皮细胞中由TRPM8受体介导的Ca2+内流[116], 从而缓解寒冷刺激对支气管上皮细胞的伤害。
6 结语与展望到目前为止, 从自然界中已发现靶向TRP通道的天然调节剂100余种, 主要包括生物碱类、萜类、酚类、多肽和黄酮类等成分, 涉及到动植物等70余种 (表 1)[1, 12, 17, 32, 34, 36, 38, 41-43, 47, 48, 52, 53, 60, 62, 63, 66, 70, 71, 81, 83, 85-88, 90, 91, 93, 98-100, 108, 111, 112, 114, 117-121]。大部分调节剂通过激活或抑制TRP通道, 提高或降低胞内Ca2+水平, 致使神经末梢脱敏、诱导内源性物质释放等; 在体内动物实验中表现为镇痛、抗炎、抗抑郁、抗肿瘤、抑制细胞增殖、降血糖和保护神经系统等活性。
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Table 1 Action information of natural modulators targeting transient receptor potential (TRP) channels ("+", activation; "-", inhibition; "+/-", dual regulation) |
据统计, 在1981~2014年间上市的小分子新药中, 有33%直接来源于天然产物及其衍生物, 另外还有32%的新药是以天然产物作为药效团的合成或仿生药物[122]。这些数据毫无疑义地证明了天然产物是新药发现的一个重要来源。TRP通道的发现及功能的阐明为新药的研发提供了新的靶点和视角, 而诸多靶向TRP通道天然调节剂的发现也增强了人们开发该类创新药物的信心。我国天然药物的资源丰富并有长期的积累, 如何利用这些丰富的资源, 去发现更多、活性更强的TRP通道的天然调节剂是一项长期而艰苦的工作。结合我国的传统中医药理论及现代生物学技术, 运用先进的分离纯化方法, 以生物活性为导向进行靶向的分离、纯化, 并结合体内外药理学验证实验, 将有助于对TRP通道天然调节剂的快速和高效发现。目前, 针对天然来源的TRP通道小分子调节剂的研究还比较浅显, 除了缺乏功能明确的分子靶标, 亦缺少对调节剂构效关系的系统分析与研究, 因此开展对活性先导化合物的结构修饰与优化等方面的研究, 阐明其构效关系及主要药效团, 对于靶向TRP通道的创新药物研发具有重要的指导意义。另外, 很多TRP通道亚型的精细结构、生物学功能及其与疾病的相关性也有待于研究, 利用不断发现的天然调节剂对TRP通道蛋白的结构和功能进行深入研究, 也是一项具有创新性的科学研究活动。
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