Phosphatidylinositol 3 kinase activation and AMPA receptor subunit trafficking underlie the potentiation of miniature EPSC amplitudes triggered by the activation of L-type calcium channels
Phosphatidylinositol 3 kinase activation and AMPA receptor subunit trafficking underlie the potentiation of miniature EPSC amplitudes triggered by the activation of L-type calcium channels
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DOI：
10.1523/jneurosci.4101-05.2006
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发表时间：
2006-05-17
影响因子：
5.3
通讯作者：
Wyllie, David J. A.
中科院分区：
文献类型：
--
作者：
Baxter, Andrew W.;Wyllie, David J. A.
我们发现了一种机制，通过这种机制，大鼠海马器官型切片培养CA1锥体神经元中的微型EPSCs （mEPSCs）的振幅在-80至+20 mV的一系列去极化电压脉冲后被增强了大约两倍。mEPSC振幅的增加是由l型钙通道的激活触发的，与NMDA受体（NMDAR）的激活无关，但也需要钙从细胞内储存中释放出来。去极化脉冲诱导的增强作用不会改变mepsc的动力学参数。这种增强的诱导阶段涉及磷脂酰肌醇3激酶（PI3激酶）的激活，因为它在PI3激酶抑制剂wortmannin和2-(4-morpholinyl)-8-苯基- 4h -1-苯并吡喃-4-one （LY294002）的存在下被完全阻断。此外，我们发现去极化脉冲增强的维持阶段需要持续的PI3激酶活性，因为wortmannin或LY294002的应用会导致mepsc振幅控制水平的逆转。最后，我们证明了mEPSC振幅的增加是由功能性AMPA受体（AMPAR）的表达增加介导的，因为增强被n -乙基马酰亚胺、肉毒毒素A和各种短序列肽阻断，这些短序列肽破坏了AMPAR亚基与参与将其运送到细胞膜的蛋白质的相互作用。我们的数据与PI3激酶和膜融合/运输事件在协调由AMPA受体介导的突触强度变化中起关键作用的观点是一致的，这些变化是由突触后钙浓度的改变触发的，无论这些变化是通过nmdar依赖还是nmdar独立的途径启动的。
We have characterized a mechanism by which the amplitudes of miniature EPSCs (mEPSCs) in CA1 pyramidal neurons in rat hippocampal organotypic slice cultures are potentiated by approximately twofold after a series of depolarizing voltage pulses from -80 to +20 mV. The increase in mEPSC amplitudes is triggered by the activation of L-type calcium channels and is independent of NMDA receptor (NMDAR) activation but also requires calcium release from intracellular stores. The potentiation induced by depolarizing pulses does not alter the kinetic parameters of mEPSCs. The induction phase of this potentiation involves phosphatidylinositol 3 kinase (PI3 kinase) activation because it is blocked completely in the presence of the PI3 kinase inhibitors wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). Furthermore, we show that the maintenance phase of depolarizing pulse potentiation requires continued PI3 kinase activity because the application of either wortmannin or LY294002 results in a reversal to control levels of the amplitudes of mEPSCs. Finally, we demonstrate that the increase in mEPSC amplitudes is mediated by the increased expression of functional AMPA receptors (AMPARs) because the potentiation is blocked by N-ethylmaleimide, botulinum toxin A, and a variety of short-sequence peptides that disrupt the interaction of AMPAR subunits with proteins involved with the trafficking of these to the cell membrane. Our data are consistent with the notion that PI3 kinase and membrane fusion/trafficking events play a pivotal role in coordinating changes in synaptic strength, mediated by AMPA receptors, which are triggered by alterations in postsynaptic calcium concentrations whether these changes are initiated via NMDAR-dependent or NMDAR-independent routes.