Involvement of calcium/calmodulin-dependent protein kinases in the setting of a molecular switch involved in hippocampal LTP
Involvement of calcium/calmodulin-dependent protein kinases in the setting of a molecular switch involved in hippocampal LTP
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DOI：
10.1016/s0028-3908(98)00058-6
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发表时间：
1998-04-01
影响因子：
4.7
通讯作者：
Collingridge, GL
中科院分区：
文献类型：
--
作者：
Bortolotto, ZA;Collingridge, GL
长时程增强（LTP）是突触可塑性的一种形式，通常与学习和记忆有关。使用蛋白激酶抑制剂的研究表明，几种激酶在海马CA 1区诱导LTP中的功能作用，尽管任何给定激酶的确切作用尚未完全确定。在这里，我们报告，选择性钙/钙调素依赖性蛋白激酶（CaMK）抑制剂KN-62对LTP有两个不同的行动。如前所述，KN-62（3 μ M）阻止了LTP的诱导。在这里，我们发现KN-62还可以阻止由（S）-α-甲基-4-羧基苯甘氨酸（MCPG）敏感的代谢型谷氨酸（mGlu）受体的突触激活引发的分子开关的设置。这项工作有两个方面可能令人惊讶。首先，通过KN-62（1 μ M）亚阈值浓度抑制LTP本身的诱导来防止分子开关的设置。第二，通过在特异性NMDA受体拮抗剂（R）-2-氨基-5-膦酰基戊酸酯（AP 5）存在下递送破伤风（100 Hz，1 s）来设置分子开关，降低了LTP对KN-62的敏感性，使得在3 μ M的浓度下它不再阻断诱导（尽管在10 μ M时它阻断了）。在AP 5存在下传递的破伤风的这种调节作用被MCPG（200 μ M）阻止。这些数据揭示了意想不到的复杂性参与KN-62敏感的过程（大概是CaMKII）在诱导LTP。他们认为KN-62敏感过程的激活导致（至少）两个磷酸化步骤，在单个突触内的突触可塑性中具有根本不同的作用。他们还提出了CaMKII是MCPG敏感分子开关机制的组成部分的可能性。(C)1998爱思唯尔科技有限公司版权所有。
Long-term potentiation (LTP) is the form of synaptic plasticity most commonly associated with learning and memory. Studies using protein kinase inhibitors have suggested functional roles for several kinases in the induction of LTP in the CA1 region of the hippocampus, though the precise role of any given kinase has yet to be fully established. Here we report that the selective calcium/calmodulin-dependent protein kinase (CaMK) inhibitor KN-62 has two distinct actions on LTP. As reported previously, KN-62 (3 mu M) prevented the induction of LTP. Here we show that KN-62 also prevents the setting of a molecular switch, initiated by the synaptic activation of (S)-alpha-methyl-4-carboxyphenylglycine (MCPG)-sensitive metabotropic glutamate (mGlu) receptors. There are two aspects of this work which might be considered surprising. First, the setting of the molecular switch was prevented by a concentration of KN-62 (1 mu M) subthreshold for the inhibition of the induction of LTP per se. Second, the setting of the molecular switch, by the delivery of a tetanus (100 Hz, 1 s) in the presence of a specific NMDA receptor antagonist (R)-2-amino-5-phosphonopentanoate (AP5), reduced the sensitivity of LTP to KN-62, such that at a concentration of 3 mu M it no longer blocked induction (though at 10 mu M it did). This conditioning effect of a tetanus, delivered in the presence of AP5, was prevented by MCPG (200 mu M). These data reveal unexpected complexities in the involvement of KN-62-sensitive processes (presumably CaMKII) in the induction of LTP. They suggest that activation of KN-62-sensitive processes leads to (at least) two phosphorylation steps with fundamentally different roles in synaptic plasticity within a single synapse. They also raise the possibility that CaMKII is an integral part of the MCPG-sensitive molecular switch mechanism. (C) 1998 Elsevier Science Ltd. All rights reserved.