Glycogen synthase kinase 3 activity mediates neuronal pentraxin 1 expression and cell death induced by potassium deprivation in cerebellar granule cells
Glycogen synthase kinase 3 activity mediates neuronal pentraxin 1 expression and cell death induced by potassium deprivation in cerebellar granule cells
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DOI：
10.1124/mol.104.007062
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发表时间：
2005-04-01
影响因子：
3.6
通讯作者：
Trullas, R
中科院分区：
文献类型：
--
作者：
Enguita, M;DeGregorio-Rocasolano, N;Trullas, R
当钾浓度降至去极化水平以下时，神经元五角蛋白1(NP1)的表达是成熟小脑颗粒神经元凋亡细胞死亡程序的一部分。NP1是一种与急性时相免疫反应中的五肽同源的糖蛋白，参与突触发生和突触重塑。然而，它如何参与神经细胞凋亡的过程仍不清楚。我们已经研究了已知的控制神经细胞死亡和存活的信号通路是否影响NP1的表达。胰岛素样生长因子I激活磷脂酰肌醇3-激酶/Akt(PI-3-K/AKT)通路和药物阻断应激激活的c-jun氨基末端激酶(JNK)均可提供一过性神经保护，使其免受非去极化浓度钾引起的细胞死亡。然而，这两种神经保护治疗都不能阻止钾缺乏时NP1的过度表达，这表明非去极化条件激活了额外的细胞死亡信号通路。在不改变JNK的情况下抑制p38丝裂原活化蛋白激酶的磷酸化，既不会减少细胞死亡，也不会在非去极化条件下抑制NP1的过度表达。相反，损害糖原合成酶激酶3(GSK3)的活性可以完全阻断钾耗竭引起的NP1的过度表达，并对细胞死亡提供短暂的保护。此外，同时对JNK和GSK3活性的药理阻断提供了长期的保护，防止钾耗竭引起的细胞死亡。这些结果表明，JNK和GSK3信号通路都是缺钾激活细胞死亡的主要途径，NP1的过度表达不受PI-3-K/AKT或JNK通路的调节，而受GSK3活性的调节。
Expression of neuronal pentraxin 1 ( NP1) is part of the apoptotic cell death program activated in mature cerebellar granule neurons when potassium concentrations drop below depolarizing levels. NP1 is a glycoprotein homologous to the pentraxins of the acute phase immune response, and it is involved in both synaptogenesis and synaptic remodeling. However, how it participates in the process of apoptotic neuronal death remains unclear. We have studied whether the signaling pathways known to control neuronal cell death and survival influence NP1 expression. Both activation of the phosphatidylinositol 3-kinase/ Akt ( PI-3-K/AKT) pathway by insulin-like growth factor I and pharmacological blockage of the stress activated c-Jun NH2-terminal kinase (JNK) offer transitory neuroprotection from the cell death evoked by nondepolarizing concentrations of potassium. However, neither of these neuroprotective treatments prevents the overexpression of NP1 upon potassium depletion, indicating that nondepolarizing conditions activate additional cell death signaling pathways. Inhibiting the phosphorylation of the p38 mitogen- activated protein kinase without modifying JNK, neither diminishes cell death nor inhibits NP1 overexpression in nondepolarizing conditions. In contrast, impairing the activity of glycogen synthase kinase 3 ( GSK3) completely blocks NP1 overexpression induced by potassium depletion and provides transient protection against cell death. Moreover, simultaneous pharmacological blockage of both JNK and GSK3 activities provides long-term protection against the cell death evoked by potassium depletion. These results show that both the JNK and GSK3 signaling pathways are the main routes by which potassium deprivation activates apoptotic cell death, and that NP1 overexpression is regulated by GSK3 activity independently of the PI-3-K/AKT or JNK pathway.