Lithium inhibits glycogen synthase kinase-3 by competition for magnesium
Lithium inhibits glycogen synthase kinase-3 by competition for magnesium
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DOI：
10.1006/bbrc.2000.4169
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发表时间：
2001-01-26
影响因子：
3.1
通讯作者：
Harwood, AJ
中科院分区：
文献类型：
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作者：
Ryves, WJ;Harwood, AJ
锂（Li（+））抑制蛋白激酶糖原合成酶激酶-3（GSK-3）的机制尚不清楚。在这里，我们证明Li（+）是GSK-3相对于镁（Mg（2+））的竞争性抑制剂，但不是底物或ATP。这种抑制模式在哺乳动物和网骨藻GSK-3同种型之间是保守的，并且不经历其他I族金属离子。因此，Li（+）抑制的效力取决于Mg（2+）浓度。我们还发现GSK-3对ATP螯合游离Mg（2+）敏感，当ATP浓度超过Mg（2+）时，GSK-3被逐渐抑制。考虑到ATP和Mg 2+的细胞浓度，我们的结果表明Li+对GSK-3活性的体内影响比体外研究预期的更大，这可能是其用于治疗抑郁症的相关因素。(C)北京：科学出版社.
The mechanism by which lithium (Li(+)) inhibits the protein kinase glycogen synthase kinase-3 (GSK-3) is unknown. Here, we demonstrate that Li(+) is a competitive inhibitor of GSK-3 with respect to magnesium (Mg(2+)), but not to substrate or ATP. This mode of inhibition is conserved between mammalian and Dictyostelium GSK-3 isoforms, and is not experienced with other group I metal ions. As a consequence, the potency of Li(+) inhibition is dependent on Mg(2+) concentration. We also found that GSK-3 is sensitive to chelation of free Mg(2+) by ATP and is progressively inhibited when ATP concentrations exceed that of Mg(2+). Given the cellular concentrations of ATP and Mg2+, our results indicate that Li+ will have a greater effect on GSK-3 activity in vivo than expected from in vitro studies and this may be a factor relevant to its use in the treatment of depression. (C) 2001 Academic Press.