The role of reversible oxidative protein modification in regulation of neurotransmitter systems

活性氧是由细胞中的氧代谢过程产生的。虽然过多的活性氧导致氧化损伤，有助于许多疾病的病理发展，活性氧在生理调节中的确切作用仍有待确定。大脑占总体重的不到2%，但消耗约20%的身体氧气。这种高耗氧速率导致活性氧物质的高基础水平。这些活性氧可以修饰蛋白质中的氨基酸，影响大脑中蛋白质的功能。神经递质通过突触将信号从一个神经元传递到另一个神经元，这是神经元功能的重要基础。神经递质在神经元中合成后，囊泡神经递质转运蛋白将它们包装到突触囊泡中，然后释放它们，靶向其他神经元中的受体。这些转运蛋白是神经元之间化学传递的重要组成部分。最近，我们发现活性氧可以引起这些囊泡神经递质转运蛋白的氧化修饰，这表明突触蛋白的氧化修饰可能有助于调节神经递质系统。从这一发现，我们可以假设，氧化修饰的囊泡神经递质转运蛋白的活性氧可能有一部分发挥转运活性。我们现在将集中研究这种氧化修饰是否确实在转运蛋白活性的调节中起重要作用。我们还将确定这些转运蛋白中可以被活性氧修饰的单个氨基酸。我们的研究计划使我们能够系统地分析活性氧在神经传递和大脑功能调节中的潜在作用。这项拟议的研究将显着增加我们对活性氧在调节神经元功能的理解，特别是将有助于更好地了解活性氧信号在大脑生理功能的性质。

Reactive oxygen species are produced by oxygen metabolic processes in the cell. Although excessive reactive oxygen species that cause oxidative damage contribute to pathological development in many diseases, the precise role of reactive oxygen species in physiological regulation remains to be determined. The brain constitutes less than 2% of total body weight, but consumes about 20% of total body oxygen. This high oxygen consumption rate leads to a high base level of reactive oxygen species. Those reactive oxygen species can modify amino acids in proteins and affect protein functioning in the brain. Neurotransmitters transport signals from one neuron to another via synapses, which is the essential basis of neuronal functioning. After neurotransmitters are synthesized in neurons, vesicular neurotransmitter transporters pack them into synaptic vesicles and later release them, targeting receptors in other neurons. These transporters are essential components of chemical transmission between neurons. Recently we found that reactive oxygen species can cause oxidative modification of these vesicular neurotransmitter transporters, suggesting that oxidative modification of synaptic proteins may contribute to regulation of neurotransmitter systems. From this finding, we can hypothesize that oxidative modification of vesicular neurotransmitter transporters by reactive oxygen species may have a part to play in transporter activity. We will now focus on studying if this oxidative modification does indeed have an important role in regulation of transporter activity. We will also identify the individual amino acids in those transporters that can be modified by reactive oxygen species. Our research program allows us to systematically analyze the potential role of reactive oxygen species in regulation of neurotransmission and in brain functioning. This proposed research will significantly increase our understanding of reactive oxygen species in regulating neuronal function and will particularly facilitate a greater understanding of the nature of reactive oxygen specie signaling in physiological functioning of the brain.