Inhibition of AKT Signaling Alters βIV Spectrin Distribution at the AIS and Increases Neuronal Excitability

Frontiers in Molecular Neuroscience

Cihan B. Kayasandik²  Saurabh Prasad³  Pooran Negi⁴  Demetrio Labate⁴  Nickolas Fularczyk⁴  Fernanda Laezza⁵  Jessica Di Re⁵  T. F. James⁵  Federico Scala⁵  Mate Marosi⁵  Miroslav N. Nenov⁵  Wei-Chun J. Hsu⁶ 

[1] Biochemistry and Molecular Biology Graduate Program, Graduate School of Biomedical Sciences, University of Texas Medical Branch, Galveston, TX, United States;Department of Computer Engineering, Istanbul Medipol University, Istanbul, Turkey;Department of Electrical and Computer Engineering, University of Houston, Houston, TX, United States;Department of Mathematics, University of Houston, Houston, TX, United States;Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, United States;M.D./Ph.D. Combined Degree Program, Graduate School of Biomedical Sciences, University of Texas Medical Branch, Galveston, TX, United States;

关键词: AIS plasticity;    support vector machine classification;    confocal imaging;    GSK3 – glycogen synthase kinase 3;    WEE1 kinase;    patch clamp electrophysiology;   

DOI  :  10.3389/fnmol.2021.643860

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown