Converting the sodium-potassium pump into a shutdown channel

中枢神经元经历扩散性去极化(SD)，在急性代谢需求时关闭大脑功能。SD以1-5 mm/min的速度在灰质中迁移，并在昆虫(可能也包括脊椎动物)中进化，在缺氧、头部损伤或突然温度变化的压力下导致大脑沉默。SD通过减少运动来保护行为，但如果持续许多分钟，就会杀死神经元。SD紧跟在Na/K ATPase失效之后，但将其与巨大的内向电流驱动SD联系起来的分子机制尚不清楚和难以捉摸。阻断电压或配基门控通道并不能阻止SD样的“缺氧”去极化(AD)。已知海洋毒素(Palyoxin，Ptox)的分子作用能以皮摩尔量与Na/K泵结合，将其从需要ATP的转运体转换为开放的阳离子通道。在小鼠或大鼠的活体脑片上，我们显示的突然的Na+内流和K+外流仅在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 ATPase转化为驱动SD的通道，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的关闭提供洞察力。

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.