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

细胞内的氧代谢过程产生了活性氧物种。尽管导致氧化损伤的过多的活性氧物种在许多疾病的病理发展中起到了作用，但活性氧物种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%，但消耗的氧气约占全身氧气的20%。这种高的耗氧率导致了活性氧物种的高碱度。这些活性氧物种可以修饰蛋白质中的氨基酸，影响蛋白质在大脑中的功能。 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，突触是神经元功能的基本基础。神经递质在神经元合成后，囊泡神经递质转运体将它们包装成突触小泡，然后将它们释放出来，靶向其他神经元的受体。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，活性氧物种可以引起这些囊泡性神经递质转运体的氧化修饰，提示突触蛋白的氧化修饰可能有助于神经递质系统的调节。根据这一发现，我们可以假设，活性氧对囊泡神经递质转运体的氧化修饰可能在转运体活性中发挥作用。我们现在将重点研究这种氧化修饰是否真的在调节转运蛋白活性方面发挥重要作用。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物种在调节神经传递和大脑功能方面的潜在作用。这项拟议的研究将大大增加我们对活性氧物种在调节神经元功能中的理解，特别是将有助于更好地理解活性氧物种信号在大脑生理功能中的性质。

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.