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

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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.