Converting the sodium-potassium pump into a shutdown channel

将钠钾泵转变为关闭通道

• 批准号: RGPIN-2017-04624
• 负责人: Andrew, Robert
• 金额: $ 1.89万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629287
• 关键词: Converting; sodium; potassium; pump; into

Central neurons undergo spreading depolarization (SD) which shuts down brain function during acute metabolic demand. SD migrates across gray matter at 1-5 mm/min and has evolved in insects (and perhaps in the vertebrates) to induce brain silence under the stress of anoxia, head injury or sudden temperature change. SD is behaviorally protective by reducing movement but can kill neurons if it lasts many minutes. SD immediately follows failure of the Na/K ATPase but the molecular mechanism linking it the massive inward current driving SD is unknown and elusive. Blockade of voltage- or ligand-gated channels does not prevent the SD-like `anoxic` depolarization (AD). The molecular action the marine poison (palytoxin, Ptox) is known to specifically bind the Na/K pump at picomolar amounts, converting it from an ATP-requiring transporter to an open cationic channel. The sudden Na+ influx and K+ efflux we show emulates SD at a mere 10-100 nM in live brain slices of mouse or rat. Our hypothesis is that severe metabolic stress likewise converts the Na/K ATPase into a channel that drives SD, evoking the neuronal shutdown that is prevalent across animal classes. Thus the molecular action of Ptox can provide insight to CNS shutdown.

中枢神经元经历扩张性去极化（SD），在急性代谢需求时关闭脑功能。SD以1-5毫米/分钟的速度在灰质中迁移，并在昆虫（也许在脊椎动物中）中进化，在缺氧、头部损伤或突然温度变化的压力下诱导大脑沉默。SD通过减少运动来保护行为，但如果持续很长时间，就会杀死神经元。在Na/K atp酶失效后立即发生SD，但将其与驱动SD的大量内向电流联系起来的分子机制尚不清楚。电压或配体门控通道的阻断不能阻止sd样的“缺氧”去极化（AD）。已知海洋毒物（palytoxin, Ptox）的分子作用是特异性地以皮摩尔量结合Na/K泵，将其从需要atp的转运体转化为开放的阳离子通道。我们所显示的Na+的突然流入和K+的突然流出在小鼠或大鼠的活脑切片中仅在10-100 nM处模拟SD。我们的假设是，严重的代谢应激同样会将Na/K atp酶转化为驱动SD的通道，从而引发在动物类别中普遍存在的神经元关闭。因此，Ptox的分子作用可以为CNS关闭提供线索。