Inhibition of AKT Signaling Alters βIV Spectrin Distribution at the AIS and Increases Neuronal Excitability.
Inhibition of AKT Signaling Alters βIV Spectrin Distribution at the AIS and Increases Neuronal Excitability.
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DOI：
10.3389/fnmol.2021.643860
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发表时间：
2021
影响因子：
4.8
通讯作者：
Laezza F
中科院分区：
文献类型：
--
作者：
Di Re J;Hsu WJ;Kayasandik CB;Fularczyk N;James TF;Nenov MN;Negi P;Marosi M;Scala F;Prasad S;Labate D;Laezza F
轴突起始段(AIS)是神经元放电所需的一个高度调控的亚细胞区域。AIS蛋白组成和分布的变化是结构可塑性的一种形式，它有力地调节神经元的活动，可能是几种神经精神和神经退行性疾病的基础。尽管AIS蛋白在生理和病理生理学上具有相关性，但对AIS蛋白分布的信号通路的研究仍然很少。在这里，我们使用共聚焦成像和原代海马神经元的全细胞膜片钳电生理学来研究AIS蛋白组成和神经元放电如何随着针对AKT/GSK3途径的特定激酶抑制剂的反应而变化，此前已有证据表明AKT/GSK3途径可以使AIS蛋白磷酸化。基于图像的特征代表了电压门控Na+通道、锚蛋白G、βIV血影蛋白和细胞黏附分子神经筋膜蛋白的细胞模式分布，揭示了βIV血影蛋白是对AKT/GSK3通路抑制最敏感的AIS蛋白。在这一通路中，对βIV光谱蛋白定位及其在神经元内的亚细胞分布的影响最大的是三氯核苷对AKT的抑制，这一表型支持向量机分类能够准确地区分对照。用三七叶碱治疗也能增加初级海马神经元的兴奋性。因此，AKT通路内信号机制的扰动导致βIV血影蛋白分布和神经元放电的变化，可能与神经精神和神经退行性疾病有关。
The axon initial segment (AIS) is a highly regulated subcellular domain required for neuronal firing. Changes in the AIS protein composition and distribution are a form of structural plasticity, which powerfully regulates neuronal activity and may underlie several neuropsychiatric and neurodegenerative disorders. Despite its physiological and pathophysiological relevance, the signaling pathways mediating AIS protein distribution are still poorly studied. Here, we used confocal imaging and whole-cell patch clamp electrophysiology in primary hippocampal neurons to study how AIS protein composition and neuronal firing varied in response to selected kinase inhibitors targeting the AKT/GSK3 pathway, which has previously been shown to phosphorylate AIS proteins. Image-based features representing the cellular pattern distribution of the voltage-gated Na+ (Nav) channel, ankyrin G, βIV spectrin, and the cell-adhesion molecule neurofascin were analyzed, revealing βIV spectrin as the most sensitive AIS protein to AKT/GSK3 pathway inhibition. Within this pathway, inhibition of AKT by triciribine has the greatest effect on βIV spectrin localization to the AIS and its subcellular distribution within neurons, a phenotype that Support Vector Machine classification was able to accurately distinguish from control. Treatment with triciribine also resulted in increased excitability in primary hippocampal neurons. Thus, perturbations to signaling mechanisms within the AKT pathway contribute to changes in βIV spectrin distribution and neuronal firing that may be associated with neuropsychiatric and neurodegenerative disorders.
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影响因子：
4.7
作者：
Crofton EJ;Nenov MN;Zhang Y;Scala F;Page SA;McCue DL;Li D;Hommel JD;Laezza F;Green TA
通讯作者：
Green TA
影响因子：
3.7
作者：
Hsu WC;Nenov MN;Shavkunov A;Panova N;Zhan M;Laezza F
通讯作者：
Laezza F
DOI：
10.1083/jcb.137.3.703
发表时间：
1997-05-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Garver TD;Ren Q;Tuvia S;Bennett V
通讯作者：
Bennett V
DOI：
10.1523/jneurosci.4064-11.2011
发表时间：
2011-11-09
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Grubb MS;Shu Y;Kuba H;Rasband MN;Wimmer VC;Bender KJ
通讯作者：
Bender KJ
影响因子：
4.8
作者：
Hsu, Wei-Chun J.;Scala, Federico;Laezza, Fernanda
通讯作者：
Laezza, Fernanda