Reactive oxygen species‐dependent down regulation of protein phosphatase contributes to tyrosine hydroxylase activation by intermittent hypoxia

Abstract

In a previous study we showed that intermittent hypoxia (IH) activates tyrosine hydroxylase (TH), the rate‐limiting enzyme in catecholamine biosynthesis via increased phosphorylation of Ser‐40 without altering total TH protein (Kumar et al., J. Appl. Physiol. 95: 536‐544, 2003). In the present study, we examined the role of protein phosphatase(s) in IH‐evoked TH activation in the brainstem of rats. IH increased TH activity in the medullary regions of the brainstem associated with regulation of cardio‐respiratory systems. This increase TH activity was associated with elevation of dopamine (DA) levels, and increase in TH phosphorylation at Ser‐31 and Ser‐40. IH also resulted in the down‐regulation of protein phosphatase 2A (PP2A) expression and activity. Reactive oxygen species (ROS) were elevated in the brainstem regions in IH exposed rats. Anti‐oxidants prevented IH‐induced down‐regulation of PP2A as well as increases in serine phosphorylation of TH with a concomitant reduction of TH activity and DA to normoxic control levels. These findings demonstrate that ROS‐dependent down regulation of protein phosphatase 2A plays a critical role in IH‐induced activation of TH and increase in DA synthesis which may in part contribute to altered catecholaminergic neurotransmission in the brainstem during IH (Supported by grants from NIH HL‐89616 and HL‐90554).