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1Department of Biochemistry and 2Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106
Submitted 24 February 2003 ; accepted in final form 4 April 2003
Regulation of tyrosine hydroxylase (TH) by intermittent hypoxia (IH) was
investigated in rat pheochromocytoma 12 (PC-12) cells by exposing them to
alternating cycles of hypoxia (1% O2, 15 s) and normoxia (21%
O2, 3 min) for up to 60 cycles; controls were exposed to normoxia
for a similar duration. IH exposure increased dopamine content and TH activity
by 
42 and 56%, respectively. Immunoblot analysis revealed that
comparable levels of TH protein were expressed in normoxic and IH cells.
Removal of TH-bound catecholamines and in vitro phosphorylation of TH in
cell-free extracts by the catalytic subunit of protein kinase A (PKA)
increased TH activity in normoxic but not in IH cells, suggesting possible
induction of TH phosphorylation and removal of endogenous inhibition of TH by
IH. To assess the role of serine phosphorylation in IH-induced TH activation,
TH immunoprecipitates and extracts derived from normoxic and IH cells were
probed with anti-phosphoserine and anti-phospho-TH (Ser-40) antibody,
respectively. Compared with normoxic cells, total serine and Ser-40-specific
phosphorylation of TH were increased in IH cells. IH-induced activation of TH
and the increase in total serine and Ser-40-specific phosphorylation of TH
were inhibited by Ca2+/calmodulin-dependent protein kinase (CaMK)
and PKA-specific inhibitors but not by inhibitors of the extracellular
signal-regulated protein kinase pathway, suggesting that IH activates TH in
PC-12 cells via phosphorylation of serine residues including Ser-40, in part,
by CaMK and PKA. Our results also suggest that IH-induced phosphorylation of
TH facilitates the removal of endogenous inhibition of TH, leading to
increased synthesis of dopamine.
recurrent apnea; protein phosphorylation; protein kinase A; Ca2+/calmodulin-dependent protein kinase; catecholamine biosynthesis; PC-12 cells
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