Neurotransmitter metabolism in intermittent hypoxia

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DESCRIPTION (provided by applicant): The overall objective of the proposal is to broadly define post-translational mechanisms associated with changes in the activity of enzymes regulate the biosynthesis of neurotransmitters by chronic intermittent hypoxia (CIH). Mechanisms associated with CIH contribute to various physiological and pathophysiological conditions such as sleep apnea and leads to the development of hypertension. Neurotransmitters such as catecholamines, gamma-aminobutyric acid and amidated neuropeptides involve in the modulation of cardio-respiratory responses. The proposal tests the overall hypothesis that intermittent hypoxia alters neurotransmitter levels in the chemoafferent pathway by affecting the activity of enzymes associated with the synthesis of neurotransmitters via post-translational modifications. The hypothesis will be tested by focusing on tyrosine hydroxylase (TH), glutamate decarboxylase (GAD) and peptidylglycine alpha-amidating monooxygenase (PAM) the rate-limiting enzymes in the biosynthesis of catecholamines, GABA and amidated neuropeptides respectively. The experiments in specific aim 1 will compare the changes in the content of catecholamines (norepinephrine, dopamine and 5- hydroxytryptamine) and the activity of TH by CIH. Further, it will test the hypothesis that CIH induces phosphorylation of TH, thereby altering the enzyme activity. Potential alteration in enzymological properties of TH will be examined. Studies proposed under specific aim 2 focus on the mechanisms by which the activity of GAD is altered by CIH. Specifically, the aims of the proposed studies are to define changes in cofactor affinity and phosphorylation and dephosphorylation reactions of GAD. In specific aim 3, the effects of CIH on the redox chemistry of metal centers containing Cu2+ and the post-translational endoproteolytic modification of PAM will be investigated. Experiments will be performed in rats exposed to alternating cycles of hypoxia and normoxia for defined periods of time and rats exposed to similar duration of room air will serve as control. Tissues associated with the chemoafferent pathway such as brainstem, and carotid body will be investigated. It is anticipated that the results from studies proposed in this project may provide important new information and broaden our understanding of the effects of episodic hypoxia on enzymes associated with neurotransmitter metabolism in the chemoafferent pathway. The information from these studies will have the potential to identify new therapeutic targets for the intervention of sleep disorders associated with recurrent intermittent hypoxia.