Interaction with the NMDA receptor locks CaMKII in an active conformation
Interaction with the NMDA receptor locks CaMKII in an active conformation
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DOI：
10.1038/35081080
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发表时间：
2001-06-14
期刊：
影响因子：
64.8
通讯作者：
Schulman, H
中科院分区：
文献类型：
--
作者：
Bayer, KU;De Koninck, P;Schulman, H
钙和钙调蛋白依赖性蛋白激酶II（CaMK II）和谷氨酸受体整体参与突触可塑性的形式，可能是学习和记忆的基础。在最简单的长时程增强模型（1）中，CaMKII通过NMDA（N-甲基-D-天冬氨酸）受体的Ca 2+内流激活，然后通过诱导AMPA（α-氨基-3-羟基-5-甲基-4-异恶唑丙酸）受体的突触插入（2，3）和单通道电导增加（4）来增强突触功效。在这里，我们表明，调节CaMKII与NMDA受体亚基NR 2B上的两个位点的相互作用提供了谷氨酸诱导的激酶易位到海马神经元突触的机制。这种相互作用可以导致其他形式的增强作用：促进CaMKII对突触Ca 2+的反应;抑制CaMKII的抑制性自磷酸化;最值得注意的是，通过独立于磷酸化状态的机制直接产生持续的Ca 2 +/钙调蛋白（CaM）非依赖性（自主）激酶活性。此外，这种相互作用导致CaM的捕获，这可能会减少NMDA受体活性的下调（5）。CaMKII-NR 2B相互作用可能是其靶向蛋白直接激活激酶的原型。
Calcium- and calmodulin-dependent protein kinase II (CaMKII) and glutamate receptors are integrally involved in forms of synaptic plasticity that may underlie learning and memory. In the simplest model for long-term potentiation(1), CaMKII is activated by Ca2+ influx through NMDA (N-methyl-D-aspartate) receptors and then potentiates synaptic efficacy by inducing synaptic insertion(2,3) and increased single-channel conductance(4) of AMPA (alpha -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Here we show that regulated CaMKII interaction with two sites on the NMDA receptor subunit NR2B provides a mechanism for the glutamate-induced translocation of the kinase to the synapse in hippocampal neurons. This interaction can lead to additional forms of potentiation by: facilitated CaMKII response to synaptoc Ca2+; suppression of inhibitory autophosphorylation of CaMKII; and, most notably, direct generation of sustained Ca2+/calmodulin (CaM)-independent (autonomous) kinase activity by a mechanism that is independent of the phosphorylation state. Furthermore, the interaction leads to trapping of CaM that may reduce down-regulation of NMDA receptor activity(5). CaMKII-NR2B interaction may be prototypical for direct activation of a kinase by its targeting protein.