Regional differences in tyrosine hydroxylase activation in rat brainstem by chronic intermittent hypoxia: Role of serine phosphorylation

Abstract

We previously reported that intermittent hypoxia (IH) increases catecholamine (CA) synthesis via activation of tyrosine hydroxylase (TH), the rate-limiting enzyme in CA biosynthesis in PC12 cell cultures. In the present study, we examined whether chronic IH (CIH) exerts similar effects on TH activity in rat brainstem. Rats were exposed to 10 days of CIH or to normoxia. Brainstem tissues were harvested from control and CIH rats. TH activity and protein expression were determined in the ventral and dorsal regions of pons and medulla. CIH significantly increased TH activity in the dorsal (3.5-fold) and ventral (2.5-fold) medulla. These increases in TH activity were primarily due to specific increase in TH phosphorylation at serine 40 (dorsal) and serine 31 (ventral) residues. By contrast, TH activity decreased in the dorsal pons and was unaltered in the ventral pons without any significant alterations in serine phosphorylation. Westernblot analysis showed that TH protein level was not altered by CIH in any of the brainstem regions tested. These observations demonstrate that CIH increases TH activity by increasing TH phosphorylation of either serine-40 or serine-31 residue in the rat medulla in a region-dependent manner (supported by NIH HL-25830).