【摘 要】
：
烟碱型乙酰胆碱受体(nAChR)是由5个亚基组成的五聚体跨膜蛋白,分为肌肉型和神经型两大类,其中神经型nAChRs异常复杂,它们由不同的α和β亚基组成异源或同源型的功能性受体亚型,在脊椎动物中,至少有12个亚基,即α2～α10,β2～β4.虽然这些亚型的药理学功能截然不同,但其结构非常相似,极难区分,以致各个亚型的生理功能和药理学作用至今尚不清楚.发现和开发各个亚型的特异性分子探针,将有利于揭示和
【机 构】
：
热带生物资源教育部重点实验室(海南大学),海口市海洋药物重点实验室(海南大学) 海南海口570228
【出 处】
：
第十六届全国神经精神药理学学术会议
论文部分内容阅读
烟碱型乙酰胆碱受体(nAChR)是由5个亚基组成的五聚体跨膜蛋白,分为肌肉型和神经型两大类,其中神经型nAChRs异常复杂,它们由不同的α和β亚基组成异源或同源型的功能性受体亚型,在脊椎动物中,至少有12个亚基,即α2～α10,β2～β4.虽然这些亚型的药理学功能截然不同,但其结构非常相似,极难区分,以致各个亚型的生理功能和药理学作用至今尚不清楚.发现和开发各个亚型的特异性分子探针,将有利于揭示和阐释它们在生命体内的功能,同时有可能研发出针对上述不同疾病的治疗药物.近年来,神经型α9α10乙酰胆碱受体亚型(α9α10nAChR)备受关注.研究表明,α9α10nAChR是治疗神经痛、癌症化疗、乳腺癌、肺癌、伤口愈合、实验性自身免疫性脑脊髓炎等的新靶点.α9α10nAChR阻断剂具有治疗神经痛的效果,具有阻止神经受伤和加速受伤神经恢复的功能.角化细胞上的α9α10nAChR在伤口愈合的病理生理学过程中起着很重要的作用.α9nAChR亚基在乳腺癌组织中过表达.α9亚基变体影响支气管细胞的转化与增殖,该亚基在乳腺癌与肺癌的治疗中具有非常重要的意义.我们从海南产的将军芋螺(Conusgeneralis)中鉴定出一个新家族(αO-)芋螺毒素基因,其编码产生的成熟肽含有4个半胱氨酸(Cys)残基.我们合成了该芋螺毒素可能存在的3个二硫键异构体.过去发现的O-超家族芋螺毒素,例如由美国FDA批准的芋螺毒素治疗新药,奇考诺肽(ziconotide),含有6个Cys,是钙离子通道的强阻断剂.然而,本研究发现的这个芋螺毒素并不阻断钙离子通道,却是nAChRs的强阻断剂,对α9α10nAChR亚型的活性最强,其半阻断剂量仅为3.8 nmol· L-1.对毒素受体解离动力学进行了研究,结果表明它与α9α10nAChR的结合位点与竞争性结合的α-芋螺毒素RgIA结合的位点没有交叠.对它的3个异构体NMR结构进行了解析.在CCI神经痛模型上,该新颖芋螺毒素显示出极强的镇痛活性.该αO-新家族芋螺毒素是α9α10 nAChR的选择性强阻断剂,结构新颖,是研究该受体结构与功能的宝贵分子探针,也是很难得的治疗神经痛、癌症化疗等的原创先导药物.它的作用靶点清楚,活性强,选择性高,是开发新型镇痛药的宝贵候选药物,蕴涵着巨大的经济价值和社会效益.
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