Naturally evolved cellular adaptations to anoxia

巴克实验室正在研究允许一些脊椎动物物种，如淡水龟、金鱼和蜗牛在冬季几天到几个月无氧生存的细胞机制。我们使用肝脏和脑细胞模型来研究缺氧耐受的机制。缺氧生存的关键是关闭利用细胞活动的能量，如合成新蛋白质和维持细胞膜上的离子梯度。我们之前的研究表明，蛋白质合成减少了约90%，维持离子梯度的泵减少了75%，离子通道活性（离子穿过膜的途径）减少，在一种情况下增加。哺乳动物（人类）缺乏降低这些能量消耗反应速率的能力。然而，基本的生化途径对几乎所有物种都是共同的，当然在爬行动物（海龟）、鱼类、鸟类和哺乳动物中也是如此。我们的目标是确定负责关闭耐缺氧物种的能量消耗过程的自然细胞途径。我们已经确定了几种可能的途径，并发现在缺氧期间，涉及谷氨酸的脑兴奋性信号减少，而涉及GABA的抑制活性增加。这些结果与挥发性麻醉剂减少人类大脑活动的方式非常相似，我们可能已经发现了一种天然的麻醉机制。脑是一种可电兴奋的组织，我们也在研究不可电兴奋组织——肝脏中离子通道的缺氧调节。在下一个资助周期中，我们将继续探索脑和肝组织的电生理特性和第二信使途径，以更好地了解哪些离子通道被调节以减少能量需求并允许缺氧生存。

The Buck lab is investigating the cellular mechanisms that permit some vertebrate species, such as freshwater turtles, goldfish and snails to survive without oxygen (anoxia) for days to months during winter. We use both a liver and brain cell model to study the mechanisms of anoxia tolerance. Key to surviving anoxia is the shutting off of energy utilizing cellular activities, such as the synthesis of new proteins and maintaining ion gradients across cell membranes. We have previously shown that protein synthesis decreases by about 90%, the pump that maintains ion gradients decreases by 75%, and ion channel activity (pathways for ions to cross membranes) decreases and in one case increases. The ability to reduce the rate of these energy consuming reactions is something that mammals (humans) lack. However, basic biochemical pathways are common to almost all species, certainly amongst reptiles (turtles), fish, birds and mammals. Our goal is to determine the natural cellular pathways responsible for shutting off energy consuming processes in anoxia-tolerant species. We have already identified several possible pathways and discovered that brain excitatory signaling involving glutamate is decreased, while inhibitory activity involving GABA is increased during anoxic periods. These results are remarkably similar to the way in which volatile anesthetics reduce brain activity in humans and we may have uncovered a natural anesthetic mechanism. Brain is an electrically excitable tissue and we are also investigating anoxic regulation of ion channels in non-excitable tissue - liver. In the next grant cycle we will continue to explore the electrophysiological properties and second messenger pathways of brain and liver tissue to better understand which ion channels are regulated in a way that reduces energetic demands and permits anoxic survival.