..来自热带海洋生物芋螺毒液中的α-芋螺毒素，是烟碱乙酰胆碱受体各种亚型选择性最好的特异阻断剂，具有巨大的新药研发价值。乙酰胆碱受体介导众多中枢和外周神经系统的生理功能，是筛选诊断和治疗一大类重要疾病药物的关键靶点，如疼痛、成瘾、帕金森病、癌症等。至今对该受体各种亚型的精细结构和功能知之甚少。我们发现了一个独特的α-芋螺毒素LvIA，具有很强的镇痛活性，是迄今对α3β2和α6β2* 这两个极其相似亚型区分度最好的配体化合物，国际上之前发现的α3β2阻断剂，都同时阻断α6β2*亚型。在哺乳动物神经系统中，尤其是多巴胺神经元区域，α3β2和α6β2*两个亚型总是伴随表达，它们的结构极其相似，极难区分，却有着迥然不同的药理学功能。本项目拟通过毒素和受体的双方面突变，检测相应的功能变化，解析毒素受体相互作用位点、以及作用方式的分子机制，为LvIA应用于神经科学研究和创新药物研发提供研究基础。..

..α-Conotoxins (α-CTxs) are effective antagonists of various subtypes of nicotinic acetylcholine receptors (nAChRs) with a high selectivity, which are from venom of cone snails in tropical ocean with the realistic medicine potential. The nAChR subtypes are important in physiology of both the central and peripheral nervous system, which are key targets of drugs to treat many difficult miscellaneous diseases, such as pain, addiction, Parkinson's disease, breast and lung carcinoma etc. So far, the composition, structure and roles of nAChR subtypes remain to be elucidated. We discovered a unique and analgesic α-conotoxin LvIA from Hainan Conus lividus, which is the first ligand reported to show highest selectivity for α3β2 vs. α6β2 nAChRs until now. Previous conotoxins targeting α3β2 block α6β2* nAChR too, which are poorly selective between α3β2 vs. α6β2* nAChRs. In mammal nerve system, especially in dopaminergic regions, α6β2* nAChR accompanies α3β2 expression simultaneously. Generally, α3β2 nAChR expression overlaps with that of α6β2* nAChR. Structure of α3β2 nAChR is too similar with α6β2* nAChR to differentiate by far. However their functions are distinct different between each other. This multidisciplinary research project would focus on interaction mechanism of binding site and mode of action between α-conotoxin LvIA and its receptor α3β2 nAChR by mutations of both toxin and receptor, as well as corresponding bioassay. The results would be valuable for developing α-conotoxin LvIA as potent innovative medication of nAChRs-related diseases, and research tool of neuroscience.