Evolution of Tetrodotoxin Sensitivity

河豚毒素敏感性的演变

• 批准号: 9410565
• 负责人: Peter A. V. Anderson
• 金额: $ 25.22万
• 依托单位: University of Florida
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 1997-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9410565&HistoricalAwards=false
• 关键词: Evolution; Tetrodotoxin; Sensitivity

9410565 Anderson Animals such as sea anemones, jellyfish (Phylum Cnidaria) and flatworms (Phylum Platyhelminthes) are modern-day representatives of organisms in which the nervous system, as we know it, first evolved. As such, they present us with a window into the evolution of the early nervous system and of the various molecules that enable nervous systems to function as they do. An evolutionary approach to neurobiological questions has an added benefit inasmuch as it is possible to identify groups of relatively closely related animals that differ subtly in some aspect of their neurobiology. A case in point concerns the action of tetrodotoxin (TTX) a toxin that blocks sodium channels extremely specifically and with high affinity. Tetrodotoxin blocks sodium currents in flatworms and higher animals, but is completely ineffective in jellyfish. Thus one might ask, what are the structural differences between the flatworm and jellyfish sodium channels that account for this differential sensitivity. Armed with this information, it should be relatively easy to identify the equivalent site on mammalian sodium channels thereby enabling the development of new classes of highly specific, and highly potent anesthetics and channel blockers that target this hitherto unexploited site on this very important class of proteins. The overall aim of the proposed work is to take advantage of this difference in the TTX sensitivity of flatworm and cnidarian sodium channels to identify the requirements for TTX binding to sodium channels. In addition to using molecular cloning techniques to determine the primary structure of sodium channels from a sea anemone, and a flatworm, the PI will use conventional lipid analysis and protein biochemical techniques to determine the lipid environment of the native sodium channels in these groups, and the types of sugar moieties linked to these proteins. The PI will compare these data with equivalent data previously obtained from a jell yfish.

9410565 安德森 海葵、水母（刺胞动物门）和扁形虫（扁形动物门）等动物是现代生物的代表，我们所知道的神经系统首先在这些生物中进化。 因此，它们为我们提供了一个窗口，让我们了解早期神经系统的进化以及使神经系统发挥功能的各种分子。 神经生物学问题的进化方法有一个额外的好处，因为它有可能识别出在神经生物学的某些方面存在细微差异的相对密切相关的动物群体。 一个恰当的例子是河豚毒素（TTX）的作用，这是一种非常特异性和高亲和力的阻断钠通道的毒素。 河豚毒素可以阻断扁形虫和高等动物的钠电流，但对水母完全无效。 因此，有人可能会问，扁形虫和水母的钠通道之间的结构差异是什么，导致了这种不同的敏感性。 有了这些信息，就可以相对容易地确定哺乳动物钠通道上的等效位点，从而能够开发新的高度特异性和高效的麻醉剂和通道阻断剂，这些麻醉剂和通道阻断剂靶向这类非常重要的蛋白质上迄今尚未开发的位点。 所提出的工作的总体目标是利用扁形虫和刺胞动物钠通道的TTX敏感性的这种差异，以确定TTX与钠通道结合的要求。 除了使用分子克隆技术来确定海葵和扁形虫钠通道的一级结构外，PI还将使用常规脂质分析和蛋白质生化技术来确定这些组中天然钠通道的脂质环境以及与这些蛋白质连接的糖部分的类型。 PI将这些数据与之前从水母中获得的等效数据进行比较。