Neurotrophin-dependent regulation of voltage-gated sodium channels

电压门控钠通道的神经营养蛋白依赖性调节

基本信息

批准号：
10183336
负责人：
Fernanda Laezza
金额：
$ 59.18万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10183336
关键词：
Area Axon Behavioral Paradigm Biochemical Biochemistry Biological Assay Biological Markers Biological Psychiatry Biophysics Brain Brain-Derived Neurotrophic Factor Cell physiology Cells Cellular Assay Co-Immunoprecipitations Complement Complex Development Disease Electrophysiology (science)Ensure Experimental Models Fibroblast Growth Factor Functional disorder Future Gene Transfer Genetic Glycogen Synthase Kinase 3 Grant Image In Vitro Ion Channel Knowledge Lasers Lead Light Link Long-Term Potentiation Luciferases Macromolecular Complexes Maps Mediating Methods Microscopy Molecular Molecular Biology National Institute of Mental Health Neuronal Plasticity Neurons Nucleus Accumbens Outcome Study Pathway interactions Pharmacology Phenotype Phosphorylation Phosphorylation Site Phosphotransferases Plant Roots Predictive Factor Predisposition Property Proteins Rattus Regulation Resolution Rewards Rodent Role Scanning Signal Transduction Site Slice Sodium Channel Stimulus Synapses Therapeutic Intervention Tropomyosin Variant Viral Vector base biomarker development cellular imaging cellular targeting environmental enrichment for laboratory animals fibroblast growth factor 6 fibroblast growth factor-14 in vivo innovation interest multidisciplinary neuropsychiatric disorder neurotrophic factor novel patch clamp prevent protein protein interaction public health relevance receptor reconstitution resilience response social subcellular targeting therapeutically effective voltage

项目摘要

ABSTRACT Neuropsychiatric disorders are thought to arise from complex changes of brain plasticity. Recent evidence points toward ion channel complexes as cellular hubs of plasticity that confer disease vulnerability or protection depending on the channel regulatory state. In medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a subtype of highly vulnerable cells, neuroadaptive changes in intrinsic firing are mediated by neurotrophin brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling. Yet, the molecular mechanisms by which these changes occur are still poorly understood. Intrinsic firing in MSN relies on the integrity of the macromolecular complex of the voltage-gated Na+ (Nav) channel Nav1.6 and its accessory regulatory fibroblast growth factor 14 (FGF14) and is subject to regulation by glycogen synthase kinase 3 (GSK3) β, a downstream effector of BDNF/TrkB signaling. Here, we provide exciting new evidence for the Nav1.6, FGF14 and GSK3β as a macromolecular signaling complex downstream of BDNF/TrkB critical for MSNs neuronal plasticity. Using an array of in vitro and in cell assays, cell imaging, and electrophysiology, we show that stability, phosphorylation and functional activity of the Nav1.6 channel are proportional to the level of BDNF and the kinase activity, whereby low level of BDNF predicts resilience and high level mediates a susceptible phenotype conferred by changes in neuron firing. We will conduct a full range of biophysical, biochemical and electrophysiological studies combined with pharmacological and viral vector-based in vivo gene transfer methods to evaluate the impact of BDNF/TrkB signaling on macromolecular composition (Aim 1), subcellular targeting (Aim 2) and functional properties (Aim 3) of the Nav1.6 channel in the context of neuroadaptive plasticity of MSNs. Outcomes of these studies could potentially lead to the development of biomarkers of susceptibility to neuropsychiatric disorders by investigating molecular pathways in relevant experimental models, an area of great interest for biological psychiatry.

抽象的最近的证据。指向离子通道复合物作为塑料疾病脆弱性或保护的塑料的细胞枢纽取决于中等棘神经元（MSN）的通道调节状态（NAC）高度脆弱的细胞的亚型，内在触发的神经适应性变化是由神经营养素介导的脑衍生的神经营养因子（BDNF）/tropomyosin受体激酶B（TRKB）信号传导。但是，分子这些变化发生的机制仍然很少了解。 MSN中的固有发射取决于电压门控na+（NAV）的大分子复合物的完整性通道NAV1.6和ITSSORY调节成纤维细胞生长因子14（FGF14），并受到调节糖原合成激酶3（GSK3）β，BDNF/TRKB信号的下游效应子。令人兴奋的NAV1.6，FGF14和GSK3β作为下游的大分子信号复合物的新证据 BDNF/TRKB的MSN神经元塑料至关重要。和电生理学，我们表明NAV1.6通道的稳定性，磷酸化和功能活性为与BDNF和激酶活性的水平成正比，从而低水平 BDNF预测弹性和高水平介导由神经元射击的变化所赋予的令人震惊的表型。生物物理，生化和电力学研究范围与药理学和病毒结合基于向量的体内基因转移方法，以评估BDNF/TRKB信号对大分子的影响组成（AIM 1），亚细胞靶向（AIM 2）和功能特性（AIM 3） MSN的神经适应性塑料的背景。通过研究分子途径的神经精神疾病的敏感性生物标志物的发展在相关的实验模型中，一个对生物精神病学很感兴趣的领域。