Distribution and modulation of dynamic sodium pumps in a spinal motor network

人体中最普遍和最重要的蛋白质之一是钠泵。它大量存在于人体所有组织的每个细胞中，甚至在我们发育的受精卵中也是如此。此外，在动物界的每一个物种中也发现了相同的蛋白质，在这些物种中，它具有与人类相同的结构和功能。钠泵的作用是什么，如此重要，并且在10亿年的进化之后几乎没有变化？钠泵控制着人体细胞中两种关键离子--钠和钾的含量。在每个泵周期中，泵的作用包括将3个钠离子移出2个钾离子进入细胞。这个动作每秒重复200次，每个电池里有数百万台水泵！最终的结果是，细胞外部的钠含量很高，细胞内部的钾浓度也很高，这种情况对心脏和血管、肾脏以及大脑和脊髓的神经细胞的健康活动至关重要。每个泵周期都会消耗能量，由于钠泵的普遍存在以及它们必须始终处于活动状态，它们占我们能源使用量的50%。衡量我们对钠泵依赖程度的一个指标是当它们发生故障或其表达发生变化时会发生什么，例如在心脏病、糖尿病和运动神经元疾病中。我们仍在努力了解钠泵在这些疾病中的作用，并寻找新的药物来帮助缓解症状，但由于我们仍然不了解它们是如何工作的，这一目标严重受阻。在大脑和脊髓中尤其如此，正是在这里，我们的项目将寻求对钠泵如何在神经细胞中实际工作并控制我们的行为做出新的科学发现。人脑可能是宇宙中最复杂的结构，所以我们将使用一个简单得多的系统来探索钠泵的作用，在这个系统中，我们有非常真实的机会回答关于这些泵的重要的、尚未解决的问题。在所有脊椎动物中，小非洲爪蛙蝌蚪拥有最完整的脊髓网络。所有的神经细胞都被详细描述了，以及它们是如何连接在一起来控制动物的游泳动作的。七年前，我们发现了一种特殊类型的钠泵，只在脊髓的一些神经元中发现。它通常是安静的，只有当蝌蚪游得很快时，它才开始泵送离子。当活动停止时，增加的泵血减少了脊髓产生另一轮游泳的能力，因此泵产生了对过去活动的记忆痕迹。我们的实验旨在通过检验我们的假设来找出这些泵与其他泵的不同之处，我们的假设是，它们有一个特殊的蛋白质亚单位版本，可以在蝌蚪游泳时“感觉”到它。我们最近还发现，泵的作用可以受到某些激素和神经递质的调节，如5-羟色胺和多巴胺，这会影响脊柱游泳回路的记忆系统。我们想要更多地了解这一点，因为它与所有动物在运动过程中控制它们运动的方式有关。虽然更简单，但蝌蚪脊髓仍然极其复杂，但控制其运动的回路在组织上与哺乳动物相似。为了帮助验证我们的想法并提出新的想法，我们还将在计算机中模拟电路并添加特殊的阿尔法3钠泵。这项工作是及时而重要的，因为制造α3泵的基因(称为ATP1A3)在人类和年轻的蝌蚪中都存在。不幸的是，阿尔法3泵的突变与运动神经元疾病和一种形式的帕金森综合症有关。我们的项目有可能在钠泵研究领域发生革命性变化的时候开辟重要的新天地，并为未来的药物开发提供动力。

One of the most prevalent and important proteins in the human body is the sodium pump. It is present in high numbers in every cell across all tissues of the body, even in the fertilized egg from which we develop. Moreover, the same protein is also found in every species of the animal kingdom where it has the same structure and performs the same function as it does in humans. What do sodium pumps do that is so important, and has been remained almost unchanged after a billion years of evolution? Sodium pumps control the amounts of two key ions in the cells of the body, sodium and potassium. The pumping role involves moving 3 sodium ions out for 2 potassium ions in to cells with each pump cycle. This action is repeated up to 200 times per second, and there are millions of pumps in each cell! The end result is that the outside of cells have high sodium and the inside high potassium concentrations, a situation crucial for the healthy actions of the heart and blood vessels, the kidneys and the nerve cells of the brain and spinal cord. Each pump cycle consumes energy and because of the prevalence of sodium pumps and the fact that they must always be active, they account for a staggering 50% of our energy use.A measure of how much we rely on sodium pumps is what happens when they malfunction or their expression is altered, for example, in heart disease, diabetes and motor neuron disease. We are still trying to understand the role of sodium pumps in these diseases and find new drugs to help alleviate the symptoms, but this goal is severely hindered by the fact that we still do not understand how they work. This is especially true in the brain and spinal cord and it is here that our project will seek to make new scientific discoveries on how sodium pumps actually work in nerve cells and control our behaviours.The human brain is probably the most complex structure in the Universe so we will use a much simpler system to explore the role of sodium pumps, one in which there is a very real chance of answering the important, unresolved questions about these pumps. The small Xenopus frog tadpole has the most completely understood spinal cord network of all vertebrates. All of the nerve cells have been described in detail and also how they connect together to control the animals swimming movements. Seven years ago, we discovered a particular type of sodium pump found only in some neurons of the spinal cord. It is normally silent and only begins pumping ions when the tadpole swims fast. When the activity stops, the increased pumping reduces the ability of the spinal cord to produce another bout of swimming so the pumps produce a memory trace of past activity. Our experiments aim to find out what makes these pumps different to the others by testing our hypothesis that they have a specialised "alpha 3" version of the protein subunit that can "sense" when the tadpole is swimming. We also recently discovered that the pump action can be modulated by certain hormones and neurotransmitters, such as serotonin and dopamine, and this affects the memory system of the spinal swimming circuit. We want to learn more about this because it is relevant to the way that all animals control their movements during locomotion. Although simpler, the tadpole spinal cord is still extremely complex, but the circuit controlling its movements is similar in organisation to that found in mammals. To help validate our ideas and come up with new ones we will also simulate the circuit in a computer and add in the special alpha 3 sodium pumps. This work is timely and important because the gene that makes alpha 3 pumps (called ATP1A3) is present in both humans and young tadpoles. Unfortunately, mutations in alpha 3 pumps are linked with motor neuron disease and a form of Parkinson's syndrome. Our project has the potential to break important new ground in sodium pump research at a time when the field is being revolutionised and fuel future drug developments.