Transient increases in intracellular calcium result in prolonged site-selective increases in tau phosphorylation through a glycogen synthase kinase 3β-dependent pathway
Transient increases in intracellular calcium result in prolonged site-selective increases in tau phosphorylation through a glycogen synthase kinase 3β-dependent pathway
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DOI：
10.1074/jbc.274.30.21395
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发表时间：
1999-07-23
影响因子：
4.8
通讯作者：
Johnson, GVW
中科院分区：
文献类型：
--
作者：
Hartigan, JA;Johnson, GVW
钙离子是一种普遍存在的细胞内信号分子，通过改变细胞内钙离子的幅度和频率，同一钙离子可引起不同的反应。在这份报告中，我们研究了持续2-5分钟的钙瞬变对细胞骨架蛋白tau磷酸化状态改变的影响。钙瞬变增加导致Tau-1表位处tau磷酸化延长（1-4小时），类似于60%的增加，tau蛋白磷酸化的这些增加似乎更多地依赖于细胞内钙增加的持续时间，而较少地依赖于幅度，钙诱导的tau蛋白磷酸化的增加不依赖于蛋白质合成，也不参与反应的蛋白激酶C或钙/钙调蛋白依赖性蛋白激酶II。然而，钙诱导的tau蛋白磷酸化的增加被锂抑制，锂是糖原合成酶激酶-3 β的非竞争性抑制剂此外，钙的瞬时增加导致GSK-3 β酪氨酸磷酸化的延长增加，伴随着tau磷酸化的增加，因此，该研究首次表明细胞内钙的瞬时增加导致GSK-3 β的酪氨酸磷酸化和活化增加，其随后导致tau磷酸化状态的持续增加。
Calcium is a universal intracellular signaling molecule, Through variations in both the amplitude and frequency of intracellular calcium increases, the same calcium ion can elicit different responses. In this report, we investigated the effect of a calcium transient, lasting 2-5 min, on alterations in the phosphorylation state of the cytoskeletal protein, tau, Transient increases in calcium result in a prolonged (1-4 h) similar to 60% increase in tau phosphorylation at the Tau-1 epitope, These increases in tau phosphorylation appear to be more dependent upon the duration of the increase in intracellular calcium and less on the amplitude, The calcium-induced increases in tau phosphorylation are not dependent upon protein synthesis, nor are protein kinase C or calcium/calmodulin-dependent protein kinase II involved in the response. However, the calcium-induced increase in tau phosphorylation was inhibited by lithium, a noncompetitive inhibitor of glycogen synthase kinase-3 beta (GSK-3 beta), and by the tyrosine kinase inhibitor, genistein, Furthermore, transient increases in calcium resulted in a prolonged increase in GSK-3 beta tyrosine phosphorylation concomitant with the increase in tau phosphorylation, Therefore, this study is the first to indicate that transient increases in intracellular calcium result in increased tyrosine phosphorylation and activation of GSK-3 beta which subsequently results in a sustained increase in the phosphorylation state of tau.