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

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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.