GDNF abates serum deprivation-induced tyrosine hydroxylase Ser19 phosphorylation and activity

被引:5
作者
Kobori, Nobuhide
Moore, Anthony N.
Dash, Pramod K.
机构
[1] Univ Texas, Sch Med, Dept Neurosurg, Vivian L Smith Ctr Neurol Res, Houston, TX 77255 USA
[2] Univ Texas, Sch Med, Dept Neurobiol & Anat, Vivian L Smith Ctr Neurol Res, Houston, TX 77255 USA
关键词
catecholamine; tyrosine hydroxylase; GDNF; traumatic brain injury; Parkinson's disease; retinoic acid;
D O I
10.1016/j.brainres.2006.02.111
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
High dopamine levels can contribute to neuronal dysfunction, impair plasticity and be toxic to neuronal cells in pathological conditions. The synthesis of dopamine is regulated by phosphorylation of the rate-limiting enzyme tyrosine hydroxylase (TH) under physiological conditions, with the phosphorylation of Ser31 and Ser40 directly increasing TH activity. Although a third phosphorylation site, Ser19, does not appear to directly regulate TH activity in physiological conditions, its role in pathological conditions is poorly understood. In this study, we examined the effects of serum deprivation (to mimic loss of retrogradely/anterogradely transported target-derived neurotrophic factors following axonal injury) and glutamate receptor stimulation (to mimic excitotoxicity) on TH phosphorylation and activity in a cell line and in mesencephalic primary culture cells. In addition, we also tested whether glial cell line-derived neurotrophic factor (GDNF) can alter these changes. We demonstrate that serum-deprivation resulted in a sustained increase in Ser19 phosphorylation beginning at 3 h and lasting up to 10 h without any detectable change in Ser31 or Ser40 phosphorylation within this time frame. This increase in Ser19 phosphorylation was associated with enhanced TH activity and was due, in part, to glutamate-receptor-mediated calcium influx and possibly calcium/calmodulin-dependent protein kinase II (CaMKII) activation. Interestingly in this serum-deprivation model, GDNF blocked the increase in Ser19 phosphorylation and TH activity at the 10-h time point following serum deprivation. Furthermore, GDNF also blocked the glutamate-mediated increase in Ser19 phosphorylation in rat primary mesencephalic neuronal cultures. Taken together, these findings suggest that GDNF may reduce dopamine synthesis in pathological conditions. (c) 2006 Elsevier B.V. All rights reserved.
引用
收藏
页码:142 / 151
页数:10
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