Pattern-Specific Sustained Activation of Tyrosine Hydroxylase by Intermittent Hypoxia: Role of Reactive Oxygen Species-Dependent Downregulation of Protein Phosphatase 2A and Upregulation of Protein Kinases

Abstract

We investigated the role of protein phosphatases (PP) and protein kinases in tyrosine hydroxylase (TH) activation by two patterns of intermittent hypoxia (IH) in rat brainstem. Rats exposed to either IH(15s) (15 s, 5% O(2); 5 min, 21%O(2)) or IH(90s) (90 s each of 10% O(2) & 21%O(2)) for 10 days were used. IH(15s) but not IH(90s) caused a robust increase in TH activity, dopamine (DA) level, and TH phosphorylation at Ser-31 and Ser-40 in the medulla but not in the pons. Likewise, IH(15s) but not IH(90s) decreased activity and expression of protein phosphatase 2A (PP2A) and increased activity of multiple protein kinases. In vitro dephosphorylation with PP2A nearly abolished IH(15s)-induced increase in TH activity. IH(15s) increased generation of reactive oxygen species (ROS) in brainstem medullary regions which was nearly threefold higher than that evoked by IH(90s). Antioxidants prevented IH(15s)-induced downregulation of PP2A and increases in multiple protein kinase activity with subsequent reversal of serine phosphorylation of TH, TH activity, and DA to control levels. These findings demonstrate that IH in a pattern-specific manner activates TH involving ROS-mediated sustained increase in TH phosphorylation via downregulation of PP2A and upregulation of protein kinases.