Inhibitory Phosphorylation of GSK-3 by CaMKII Couples Depolarization to Neuronal Survival
Inhibitory Phosphorylation of GSK-3 by CaMKII Couples Depolarization to Neuronal Survival
复制标题
CaMKII 对 GSK-3 的抑制性磷酸化与去极化与神经元存活相结合
DOI：
10.1074/jbc.m110.130351
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发表时间：
2010-12-24
影响因子：
4.8
通讯作者：
Li, Mingtao
中科院分区：
文献类型：
--
作者：
Song, Bin;Lai, Bingquan;Li, Mingtao
糖原合成酶激酶-3（GSK-3）在神经元凋亡中起关键作用。该激酶的两种哺乳动物亚型GSK-3 α和GSK-3 β分别受到Ser-21和Ser-9磷酸化的抑制。去极化对神经元存活至关重要，它导致Ser-21/9磷酸化的增加和GSK-3 α/β的抑制。然而，GSK-3磷酸化在去极化依赖性神经元存活中的作用以及在去极化过程中促进GSK-3磷酸化的信号通路在很大程度上仍然未知。使用几种方法，我们发现GSK-3的两种亚型对于介导神经元凋亡都很重要。不可磷酸化的GSK-3 α/β突变体（S21 A/S9 A）促进细胞凋亡，而GSK-3 β的Ser-9肽以磷酸化依赖性方式保护神经元;这些结果表明Ser-21/9磷酸化对去极化依赖性神经元存活的关键作用。我们发现GSK-3的Ser-21/9磷酸化由Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）介导，而不是由Akt/PKB、PKA或p90（RSK）介导。CaMK II与磷酸化GSK-3 α/β相关。此外，CaMK II的促存活作用是由GSK-3磷酸化和失活介导的。这些发现确定了一种新的钙/钙调素/CaMKII/GSK-3途径，耦合去极化神经元的生存。
Glycogen synthase kinase-3 (GSK-3) plays a critical role in neuronal apoptosis. The two mammalian isoforms of the kinase, GSK-3 alpha and GSK-3 beta, are inhibited by phosphorylation at Ser-21 and Ser-9, respectively. Depolarization, which is vital for neuronal survival, causes both an increase in Ser-21/9 phosphorylation and an inhibition of GSK-3 alpha/beta. However, the role of GSK-3 phosphorylation in depolarization-dependent neuron survival and the signaling pathway contributing to GSK-3 phosphorylation during depolarization remain largely unknown. Using several approaches, we showed that both isoforms of GSK-3 are important for mediating neuronal apoptosis. Non-phosphorylatable GSK-3 alpha/beta mutants (S21A/S9A) promoted apoptosis, whereas a peptide encompassing Ser-9 of GSK-3 beta protected neurons in a phosphorylation-dependent manner; these results indicate a critical role for Ser-21/9 phosphorylation on depolarization-dependent neuron survival. We found that Ser-21/9 phosphorylation of GSK-3 was mediated by Ca2+/calmodulin-dependent protein kinase II (CaMKII) but not by Akt/PKB, PKA, or p90(RSK). CaMKII associated with and phosphorylated GSK-3 alpha/beta. Furthermore, the pro-survival effect of CaMKII was mediated by GSK-3 phosphorylation and inactivation. These findings identify a novel Ca2+/calmodulin/CaMKII/GSK-3 pathway that couples depolarization to neuronal survival.