INVOLVEMENT OF A CALCINEURIN/INHIBITOR-1 PHOSPHATASE CASCADE IN HIPPOCAMPAL LONG-TERM DEPRESSION
INVOLVEMENT OF A CALCINEURIN/INHIBITOR-1 PHOSPHATASE CASCADE IN HIPPOCAMPAL LONG-TERM DEPRESSION
复制标题
DOI：
10.1038/369486a0
复制
发表时间：
1994-06-09
期刊：
影响因子：
64.8
通讯作者：
MALENKA, RC
中科院分区：
文献类型：
--
作者：
MULKEY, RM;ENDO, S;MALENKA, RC
长期增强（LTP）是一种被认为参与学习和记忆的突触机制（1）。长时程抑制（LTD），一种突触效能的活动依赖性降低，可能是一种同样重要的机制，它允许神经网络更有效地存储信息（2，3）。在海马体中观察到的LTD的一种形式（4）需要激活突触后NMDA（N-甲基-D-天冬氨酸）受体（4，5）、突触后钙浓度的变化（5）和激活突触后丝氨酸/苏氨酸蛋白磷酸酶1（PP 1）或2A（PP 2A）（6）。PP 1或PP 2A受突触活动调节的机制尚不清楚，因为这些蛋白磷酸酶不直接受钙浓度的影响。LTD诱导可能需要激活更复杂的蛋白磷酸酶级联反应，包括Ca 2 +/钙调蛋白依赖性蛋白磷酸酶、钙调磷酸酶、其磷蛋白底物、抑制剂-1和PP 1（7，8）。我们使用钙调磷酸酶抑制剂以及加载到突触后细胞的不同形式的抑制剂-1来测试这一假设。我们的研究结果表明，钙调磷酸酶去磷酸化和失活抑制剂-1的信号通路。这反过来又增加了PP 1的活性，并有助于LTD的产生。
LONG-TERM potentiation (LTP) is a synaptic mechanism thought to be involved in learning and memory(1). Long-term depression (LTD), an activity-dependent decrease in synaptic efficacy, may be an equally important mechanism which permits neural networks to store information more effectively(2,3). One form of LTD that has been observed in the hippocampus(4) requires activation of postsynaptic NMDA (N-methyl-D-aspartate) receptors(4,5), a change in postsynaptic calcium concentration(5), and activation of postsynaptic serine/threonine protein phosphatase 1 (PP1) or 2A (PP2A)(6). The mechanism by which PP1 or PP2A is regulated by synaptic activity is unclear because these protein phosphatases are not directly influenced by calcium concentration. LTD induction may require activation of a more complex protein phosphatase cascade consisting of the Ca2+/calmodulin-dependent protein phosphatase, calcineurin, its phosphoprotein substrate, inhibitor-1, and PP1(7,8). We tested this hypothesis using calcineurin inhibitors as well as different forms of inhibitor-1 loaded into postsynaptic cells. Our results suggest a signalling pathway in which calcineurin dephosphorylates and inactivates inhibitor-1. This in turn increases PP1 activity and contributes to the generation of LTD.