四种选择性作用于酸敏感离子通道的肽类毒素的作用机制研究

选择性作用于酸敏感离子通道（ASIC）的多肽毒素在研究ASIC结构与功能关系、生理/病理的作用机制以及新药研发中具有重要的理论和应用价值，但目前尚不能满足上述研究的需要，因此其鉴定和作用机制是国际研究热点。最近，我们从多种蜘蛛毒液中鉴定到四个全新的作用于ASIC的多肽毒素（SpTx1-4）。相对于已有的作用于ASIC的多肽毒素，具有全新氨基酸序列以及不同的亚型选择性和作用模式：SpTx2-4分别选择性抑制ASIC1a、ASIC2a和ASIC3（目前后两者尚无选择性抑制剂）；SpTx-1与SpTx-2有高序列相似性，但前者采用新的作用模式，即增强 AISC1a电流而非抑制。本项目以四个多肽和相应ASIC亚型为对象，开展系统的电生理活性、结构与功能关系、相互作用位点鉴定和镇痛活性分析与比较，可发现毒素与ASIC选择性作用的新模式和新机制，为ASIC相关研究和新药研发提供分子探针和先导分子。

The acid sensing ion channels (ASICs) are a family of proton-sensing channels expressed throughout the nervous system. Their activity is linked to a variety of complex behaviors including fear, anxiety, pain, depression, learning, and memory. ASICs represent novel therapeutic targets for several clinically important disorders. Future development of potent and specific inhibitors/blockers for individual ASIC subunits will dramatically advance our understanding of the role of these channels in physiological and pathological processes, and for establishing novel therapeutic strategies for neurological diseases. Recently, we identified four peptide toxins (SpTx1-4) from Chinese spider venoms. Compared with the ASIC-targeted peptide toxins identified so far, the four toxins have very different amino acid sequences, and distinct selectivity against ASIC subunits and action mechanisms. SpTx2-4 could selectively inhibit ASIC1a, 2a and 3, respectively. It is worth noting that there are no peptide inhibitors acting on ASIC2a or ASIC3 so far. SpTx1 and SpTx2 share very similar sequences but have different action manner on ASIC1a. SpTx1 could enhance the ASIC1a current, while SpTx2 displayed inhibition effect. Therefore, SpTx1-4 represent novel specific peptide toxins targeting on ASICs. In the current proposal, the activities, structure and function relationships, binding sites and analgesic effects the four toxins will intensively investigated. The data will expand our understanding of the action mechanisms underlying the specific interaction between peptide toxins and ASICs, and will offer us new pharmacological probes helpful for ASIC-related studies and drug leads useful for therapeutic development.