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1 Kosair Children's Hospital Research Institute, Dept. of Pediatrics, University of Louisville, Louisville, KY, USA; Pharmacology & Toxicology, University of Louisville, Louisville, KY, USA
2 Kosair Children's Hospital Research Institute, Dept. of Pediatrics, University of Louisville, Louisville, KY, USA
3 Dept. of Physiology Integrative Cellulaire et Moleculaire, UMR5123, University of Lyon, Lyon, France
4 Genome Research Institute, Dept. of Genome Science, University of Cincinnatti, Cincinnatti, OH, USA
* To whom correspondence should be addressed. E-mail: evelyne.gozal{at}louisville.edu.
Tyrosine hydroxylase, a hypoxia-regulated gene may be involved in tissue adaptation to hypoxia. Intermittent hypoxia, a characteristic feature of sleep apnea, leads to significant memory deficits, as well as to cortex and hippocampal apoptosis that are absent following sustained hypoxia. To examine the hypothesis that sustained and intermittent hypoxia induce different catecholaminergic responses, changes in tyrosine hydroxylase mRNA, protein expression, and activity were compared in various brain regions of male rats exposed from 6h, 1, 3 and 7 days of sustained (10% O2), intermittent (alternating room air and 10% O2) hypoxia or to normoxia. Tyrosine hydroxylase activity, measured at 7 days, increased in the cortex as follows: sustained > intermittent > normoxia. Furthermore, activity decreased in the brainstem, and was unchanged in other brain regions of sustained hypoxia-exposed rats, as well as in all regions from animals exposed to intermittent hypoxia, suggesting stimulus-specific and heterotopic catecholamine regulation. In the cortex, tyrosine hydroxylase mRNA expression was increased while protein expression remained unchanged. In addition, significant differences in the time course of cortical ser 40 TH phosphorylation were present in the cortex, suggesting that intermittent and sustained hypoxia induced enzymatic activity differences are related to different phosphorylation patterns. We conclude that long-term hypoxia induces site-specific changes in tyrosine hydroxylase activity, and that intermittent hypoxia elicits reduced tyrosine hydroxylase recruitment and phosphorylation compared to sustained hypoxia. Such changes may not only account for differences in enzyme activity, but also suggest that with differential regional brain susceptibility to hypoxia, recruitment of different mechanisms in response to hypoxia will elicit region-specific modulation of catecholamine response.
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