多肽毒素调制电压门控钠通道的作用机制研究一直是多肽毒素研究的重点。前期研究从蜘蛛毒液中鉴定到一个由链间二硫键形成的同二聚体多肽毒素，不同于已知钠通道多肽毒素，它对各钠通道亚型的调控模式有所不同：抑制Nav1.9快失活，不影响Nav1.8，抑制其他亚型如Nav1.7激活；进而发现它分别结合于Nav1.7的DIIVSD和Nav1.9的DIIIVSD，故推测它通过二聚体结构识别钠通道亚型的不同位点产生不同的调控模式，并提示DIIIVSD可能与Nav1.9快失活耦联。这与当前认知不同，因对Nav1.7等亚型，DIIIVSD主要起激活作用。鉴于此，本项目拟在毒素结构、作用模式和相互作用位点三个层面深入探究，以证实上述推测，为多肽毒素与钠通道互作的多样性和分子机制提供新知识。进一步以该毒素为分子工具建立检测模型，探究Nav1.9 DIIIVSD耦联失活的分子机制，促进Nav1.9门控调节机制研究进展。

To identify novel peptide toxins that target sodium channel and elucidate the action mechanism. Important for understand the relationship between structure and function of peptide toxins and sodium channels. Our previous study aimed to identify novel sodium channel modulator from peptide toxins. we identified a peptide that comprises two homologous inhibitor cystine knot domains separated by a disulfide bond. Compared with the previously reported toxins, it potently modulates sodium channels via a unique mode of action. Patch clamp studies indicated that homologous toxin inhibits the activation of Nav1.4-1.7 by binding to the voltage sensor of domain II， while it delays the inactivation of Nav1.9 by binding to the voltage sensor of domain III. Subsequently, in the present study, we will try to elucidate the action mechanisms through investigating the toxin structure, mode of action and construction of peptide-channel complex, and exploited the homologous toxin to probe the role of DIII VSD in Nav1.9 inactivation. This study will expand our understanding for sodium channels, and promote the relationship between structure and function of sodium channels (especially Nav1.9).