Bortolotto Z A, Collingridge G L
Department of Anatomy, School of Medical Sciences, University of Bristol, UK.
Neuropharmacology. 1998 Apr-May;37(4-5):535-44. doi: 10.1016/s0028-3908(98)00058-6.
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 microM) 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 microM) 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 microM it no longer blocked induction (though at 10 microM it did). This conditioning effect of a tetanus, delivered in the presence of AP5, was prevented by MCPG (200 microM). 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.
长时程增强（LTP）是最常与学习和记忆相关联的突触可塑性形式。使用蛋白激酶抑制剂的研究表明，几种激酶在海马体CA1区LTP的诱导中具有功能作用，尽管任何一种特定激酶的确切作用尚未完全明确。在此我们报告，选择性钙/钙调蛋白依赖性蛋白激酶（CaMK）抑制剂KN-62对LTP有两种不同作用。如先前报道，KN-62（3微摩尔）可阻止LTP的诱导。在此我们表明，KN-62还可阻止由（S）-α-甲基-4-羧基苯基甘氨酸（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定。这项工作有两个方面可能会令人惊讶。首先，分子开关的设定被抑制LTP诱导本身的阈下浓度（1微摩尔）的KN-62所阻止。其次，在存在特异性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂（R）-2-氨基-5-膦酰戊酸（AP5）的情况下，通过给予强直刺激（100赫兹，1秒）来设定分子开关，降低了LTP对KN-62的敏感性，以至于在3微摩尔浓度时它不再阻断诱导（尽管在10微摩尔时它仍能阻断）。在AP5存在下给予的强直刺激的这种条件作用效应被MCPG（200微摩尔）所阻止。这些数据揭示了KN-62敏感过程（可能是CaMKII）参与LTP诱导过程中意想不到的复杂性。它们表明，KN-62敏感过程的激活导致（至少）两个磷酸化步骤，在单个突触的突触可塑性中具有根本不同的作用。它们还提出了CaMKII是MCPG敏感分子开关机制的一个组成部分的可能性。
