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eLife:华南师大杨莉研究组发表突触研究论文

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摘要 : 2017年11月5日,国际知名期刊《eLife》杂志在线发表了华南师范大学杨莉教授研究组题为“APP modulates KCC2 expression and function in hippocampal GABAergic inhibition”的研究论文,研究阐明了淀粉样前体蛋白APP调节海马体GABA能抑制背后的突触机制。

2017年11月5日,国际知名期刊《eLife》杂志在线发表了华南师范大学杨莉教授研究组题为“APP modulates KCC2 expression and function in hippocampal GABAergic inhibition”的研究论文,研究阐明了淀粉样前体蛋白APP调节海马体GABA能抑制背后的突触机制。

研究中,利用电生理学、生物化学、分子生物学和药理学分析,研究人员发现,APP可以与KCC2——一个神经元特异性的K+ Cl-协同转运蛋白,对于Cl-体内平衡和快速的GABA能抑制是必不可少的——之间发生直接的相互作用。APP缺陷可导致总体的和膜的KCC2水平显著降低,从而导致GABA反转电位(EGABA)的去极化漂移。

海马体神经元中的突触前动作电位和抑制性突触后电流(IPSCs)的同时测量表明,受损的单一IPSC振幅归因于GABAAR的α1亚基水平的降低。重要的是,恢复KCC2在App-/-小鼠中的正常表达和功能,可恢复EGABA、GABAARα1水平以及GABAAR介导的相位性抑制。研究人员指出,APP起的作用是限制酪氨酸磷酸化和泛素化,从而限制随后的KCC2降解,从而提供了一种机制,APP通过这一机制影响KCC2丰度。总而言之,这些实验阐明了一种新的分子通路,APP通过蛋白质-蛋白质与KCC2之间的一种相互作用,介导海马体中的GABA能抑制。

原文链接:

APP modulates KCC2 expression and function in hippocampal GABAergic inhibition

原文摘要:

Amyloid precursor protein (APP) is enriched at the synapse, but its synaptic function is still poorly understood. We previously showed that GABAergic short-term plasticity is impaired in App knock-out (App-/-) animals, but the precise mechanism by which APP regulates GABAergic synaptic transmission has remained elusive. Using electrophysiological, biochemical, moleculobiological, and pharmacological analysis, here we show that APP can physically interact with KCC2, a neuron-specific K+-Cl- cotransporter that is essential for Cl- homeostasis and fast GABAergic inhibition. APP deficiency results in significant reductions in both total and membrane KCC2 levels, leading to a depolarizing shift in the GABA reversal potential (EGABA). Simultaneous measurement of presynaptic action potentials and inhibitory postsynaptic currents (IPSCs) in hippocampal neurons reveals impaired unitary IPSC amplitudes attributable to a reduction in α1 subunit levels of GABAAR. Importantly, restoration of normal KCC2 expression and function in App-/- mice rescues EGABA, GABAAR α1 levels and GABAAR mediated phasic inhibition. We show that APP functions to limit tyrosine-phosphorylation and ubiquitination and thus subsequent degradation of KCC2, providing a mechanism by which APP influences KCC2 abundance. Together, these experiments elucidate a novel molecular pathway in which APP regulates, via protein-protein interaction with KCC2, GABAAR mediated inhibition in the hippocampus.

DOI: http://dx.doi.org/10.7554/eLife.20142

作者:杨莉 点击:

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