电压门控Nav1.5钠通道在调节心肌兴奋收缩耦联、肿瘤侵袭转移等方面起重要作用，是一种重要的跨膜结构蛋白，也是治疗药物作用的重要靶标之一。JZTX-III、-IX和-XIV是从我国特有珍稀捕鸟蛛的毒液中分离到的钠离子通道调制剂。本课题将研究JZTX-III、-IX和-XIV对多种钠通道亚型的选择性以及对钠通道亚型Nav1.5通道的激活、失活、去激活等的调制作用。运用钠通道定点突变等技术和电生理技术，揭示Nav1.5通道与蜘蛛活性肽发生相互作用的关键活性位点以及对多肽呈现不同亲和力的分子机制。运用多肽固相合成技术合成多肽突变体，分析目的多肽结合Nav1.5通道的关键残基，从而提高目的多肽对钠通道亚型的选择性和专一性。在细胞和动物水平上，研究它们对乳腺癌细胞侵袭转移能力的影响及可能的分子机制。期望此课题的开展能为蜘蛛活性肽在神经生物学等方面的应用和抗肿瘤药物先导分子的设计开发提供理论基础。

Voltage-gated Nav1.5 sodium channels are an important transmembrane protein family and also be one of important targets of drugs. They are widely distributed in human tissues such as cardiomyocytes and cancer cells, and play important role in the regulation of cardiac excitation-contraction coupling and cancer metastasis. Jingzhaotoxin-III、-IX、-XIV are Nav1.5 sodium channel modulators isolated from the venom of the Chinese venomous tarantula Chilobrachys jingzhao. This study will investigate different selectivity of the three spider peptide toxins on a variety of cloned sodium ion channel subtypes and modulation effect on the human Nav1.5 sodium channels. Using electrophysiolog-ical techniques and molecular biology techniques such as sodium channel site-directed mutagenesis, we will reveal key active sites of interactions and molecular mechanism of different affinity between the Nav1.5 sodium channel subtypes and jingzhaotoxins. In order to determine the key residues of jingzhaotoxins responsible for binding Nav1.5 sodium channels and to further improve subtype selectivity and specificity of the toxins on sodium channel, mutants of native jingzhaotoxins will be synthesized by solid-phase method. We hope that this study will provide a theoretical basis in applications of spider peptide toxins in neurobiology as well as design and development of anti-cancer lead molecule.