Sustained structural change of GABAA receptor-associated protein underlies long-term potentiation at inhibitory synapses on a cerebellar purkinje neuron
Sustained structural change of GABAA receptor-associated protein underlies long-term potentiation at inhibitory synapses on a cerebellar purkinje neuron
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DOI：
10.1523/jneurosci.1981-07.2007
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发表时间：
2007-06-20
影响因子：
5.3
通讯作者：
Hirano, Tomoo
中科院分区：
文献类型：
--
作者：
Kawaguchi, Shin-Ya;Hirano, Tomoo
在中枢神经系统中，快速抑制性突触传递主要由GABA（A）受体（GABA（A）R）介导。虽然有几种类型的GABA能突触的神经元活动依赖性可塑性的报道，详细的机制是难以捉摸的。在这里，我们发现结构改变的GABA（A）R相关蛋白（GABARAP）与GABA（A）R γ 2亚基和微管蛋白的结合对于小脑浦肯野神经元（PN）抑制性突触的长时程增强（称为反弹增强（RP））至关重要。抑制GABARAP与GABA（A）R γ 2的结合或缺失GABARAP的微管蛋白结合区都损害RP。抑制微管蛋白聚合也抑制RP。因此，精确调节GABA（A）R γ 2-GABAR（A）P-微管相互作用对RP至关重要。此外，竞争性抑制GABARAP结合GABAAR γ 2后，RP建立衰减的增强反应，这表明GABARAP不仅是至关重要的诱导，但也为RP的维护。荧光共振能量转移分析表明，GABARAP经历了持续的结构变化后，短暂的PN依赖于钙/钙调蛋白依赖性蛋白激酶II（CaMKII），这是RP诱导所需的活性去极化。GABARAP进行结构改变的敏感性被GABARAP中的氨基酸替换所消除。此外，RP因替换后突变体GABARAP的表达而受损。总之，我们得出结论，GABA（A）R协会与结构改变的GABARAP下游的CaMKII激活是必不可少的RP。
Fast inhibitory synaptic transmission is predominantly mediated by GABA(A) receptor ( GABA(A)R) in the CNS. Although several types of neuronal activity- dependent plasticity at GABAergic synapses have been reported, the detailed mechanism is elusive. Here we show that binding of structurally altered GABA(A)R- associated protein ( GABARAP) to GABA(A)R gamma 2 subunit and to tubulin is critical for long-term potentiation [ called rebound potentiation ( RP)] at inhibitory synapses on a cerebellar Purkinje neuron ( PN). Either inhibition of GABARAP association with GABA(A)R gamma 2 or deletion of tubulin binding region of GABARAP impaired RP. Inhibition of tubulin polymerization also suppressed RP. Thus, precise regulation of GABA(A)R gamma 2-GABAR(A)P-microtubule interaction is critical for RP. Furthermore, competitive inhibition of GABARAP binding to GABAAR gamma 2 after the RP establishment attenuated the potentiated response, suggesting that GABARAP is critical not only for the induction but also for the maintenance of RP. Fluorescence resonance energy transfer analysis revealed that GABARAP underwent sustained structural alteration after brief depolarization of a PN depending on the activity of Ca2+/ calmodulin- dependent protein kinase II ( CaMKII), which is required for the RP induction. The susceptibility of GABARAP to undergo structural alteration was abolished by an amino acid replacement in GABARAP. Furthermore, RP was impaired by expression of the mutant GABARAP with the replacement. Together, we conclude that GABA(A)R association with structurally altered GABARAP downstream of CaMKII activation is essential for RP.