PHYSIOLOGICAL SYNERGISM BETWEEN CONOTOXINS

芋螺毒素之间的生理协同作用

• 批准号: 6564573
• 负责人: BALDOMERO M OLIVERA
• 金额: $ 14.53万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564573
• 关键词: Gastropoda; NMDA receptors; Xenopus; animal poison; calcium channel blockers; conotoxin; drug interactions; electrophysiology; goldfish; laboratory mouse; laboratory rat; ligands; molecular cloning; neuropeptides; neuropharmacology; peptide chemical synthesis; predation; protein purification; protein structure; synthetic peptide; toxin metabolism

In the last grant period, we obtained evidence that the prey-capture strategy of fish-hunting cone snails involves the use of a combination drug strategy. All fish hunting cone snails interfere with neuromuscular transmission by using multiple peptides which target important receptors and ion channels in the motor circuitry (the motor cabal). However, many fish hunting Conus species apparently also have a set of toxins in their venom which elicits excitotoxic shock in the prey, resulting in a very rapid, rigid paralysis (the lightning-strike cabal). The lightning-strike and motor cabals of two fish-hunting Conus species, Conus purpurascens and Conus magus will be analyzed in detail, and the pharmacological specificity of each Conus peptide involved will be determined. Our data suggest that individual peptides not only diverge structurally but may target different sites if two venoms are compared. We have presented preliminary evidence that fish-hunting cone snails that use a net strategy (instead of the more common hook-and-line method for catching fish) do not have the lightning-strike cabal, but instead elicit anesthetic and sedative-like effects in prey before the motor cabal acts to disrupt neuromuscular transmission. The group of peptides which generally suppress sensory systems are hypothesized to belong to the nirvana cabal, which may facilitate capture of small schools of fish by a single snail. Of exceptional interest within the nirvana cabal are the conantokins, subtype-specific NMDA receptor antagonists which have recently been shown to be potent anticonvulsants with a high protective index. Thus, the characterization of the Conus peptides which belong to the nirvana cabal may provide novel tools for suppressing the activity of the nervous system.

在最后一个赠款期间，我们获得了猎物捕获的证据 鱼锥蜗牛的策略涉及使用组合 毒品策略。所有狩猎锥蜗牛都会干扰神经肌肉 通过使用针对重要受体的多种肽传播 电动机电路中的离子通道（电动集团）。但是，很多 狩猎鱼类物种显然也有一组毒素 引起猎物兴奋性休克的毒液，导致非常 快速，僵化的麻痹（闪电般的阴谋集团）。 两个狩猎圆锥 将详细分析物种，紫红色和conus magus 每个涉及的每个圆锥肽的药理特异性将是 决定。我们的数据表明，单个肽不仅有分歧 结构上，如果比较了两个毒液，则可能针对不同的位点。 我们提出了初步证据表明鱼锥蜗牛 使用净策略（而不是更常见的挂钩方法 要捕鱼）没有闪电般的阴谋集团，而是 在马达阴谋集团之前引起麻醉和类似镇静的效果 作用是破坏神经肌肉传播的。一组肽 通常认为抑制感觉系统属于 涅rvana集团，可能有助于通过 单蜗牛。涅rvana集团内的特别感兴趣的是 Conantokins，亚型特异性NMDA受体拮抗剂，具有 最近被证明是有效的抗惊厥药，具有高保护性 指数。因此，属于圆锥肽的表征 涅rv尼加集团可以提供抑制活性的新颖工具 神经系统。