神经元和星形细胞NCX异构体/剪接变体:它们如何参与Na+和Ca2+信号传导?

IF 4.3 2区 生物学 Q2 CELL BIOLOGY
Daniel Khananshvili
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引用次数: 0

摘要

NCX1、NCX2和NCX3基因异构体及其剪接变体在大脑的不同区域具有特征性表达。NCX1-3异构体的组织特异性剪接变体在神经元和星形胶质细胞中表现出特异性表达谱,而相关的NCX异构体/剪接变体表现出Na+-和Ca2+依赖性调节的不同变构模式。一般来说,NCX1-3基因的过表达会导致神经保护作用,而其消融则会获得相反的结果。在这方面,NCX异构体/剪接变体对神经保护作用的部分贡献仍未得到解决。谷氨酸依赖的Na+进入产生Na+瞬态(响应神经元细胞活动),而Na+驱动的Ca2+进入(通过反向NCX模式)提高Ca2+瞬态。这种特殊的信号耦合模式将Na+瞬态转化为Ca2+信号,同时也是突触神经传递的一部分。这种机制是普遍感兴趣的,因为疾病相关的条件(缺血、代谢应激和中风等)触发Na+和Ca2+超载,导致下游细胞凋亡和兴奋性毒性的致命结果。最近发现的NCX变构调节机制表明,一些NCX变异可能在Na+驱动的Ca2+进入的动态耦合中起关键作用。相比之下,其他的不那么重要,甚至在改变的条件下可能是危险的(例如,代谢压力)。这个工作假设可以通过应用先进的实验方法和高度集中的计算模拟来验证。这可能允许开发基于结构的阻断剂/激活剂,可以选择性地调节预定义的NCX变异,以减轻兴奋毒性、缺血、凋亡、代谢剥夺、脑损伤和中风等危及生命的结果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Neuronal and astrocyte NCX isoform/splice variants: How do they participate in Na+ and Ca2+ signalling?

Neuronal and astrocyte NCX isoform/splice variants: How do they participate in Na+ and Ca2+ signalling?

NCX1, NCX2, and NCX3 gene isoforms and their splice variants are characteristically expressed in different regions of the brain. The tissue-specific splice variants of NCX1–3 isoforms show specific expression profiles in neurons and astrocytes, whereas the relevant NCX isoform/splice variants exhibit diverse allosteric modes of Na+- and Ca2+-dependent regulation. In general, overexpression of NCX1–3 genes leads to neuroprotective effects, whereas their ablation gains the opposite results. At this end, the partial contributions of NCX isoform/splice variants to neuroprotective effects remain unresolved. The glutamate-dependent Na+ entry generates Na+ transients (in response to neuronal cell activities), whereas the Na+-driven Ca2+ entry (through the reverse NCX mode) raises Ca2+ transients. This special mode of signal coupling translates Na+ transients into the Ca2+ signals while being a part of synaptic neurotransmission. This mechanism is of general interest since disease-related conditions (ischemia, metabolic stress, and stroke among many others) trigger Na+ and Ca2+ overload with deadly outcomes of downstream apoptosis and excitotoxicity. The recently discovered mechanisms of NCX allosteric regulation indicate that some NCX variants might play a critical role in the dynamic coupling of Na+-driven Ca2+ entry. In contrast, the others are less important or even could be dangerous under altered conditions (e.g., metabolic stress). This working hypothesis can be tested by applying advanced experimental approaches and highly focused computational simulations. This may allow the development of structure-based blockers/activators that can selectively modulate predefined NCX variants to lessen the life-threatening outcomes of excitotoxicity, ischemia, apoptosis, metabolic deprivation, brain injury, and stroke.

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来源期刊
Cell calcium
Cell calcium 生物-细胞生物学
CiteScore
8.70
自引率
5.00%
发文量
115
审稿时长
35 days
期刊介绍: Cell Calcium covers the field of calcium metabolism and signalling in living systems, from aspects including inorganic chemistry, physiology, molecular biology and pathology. Topic themes include: Roles of calcium in regulating cellular events such as apoptosis, necrosis and organelle remodelling Influence of calcium regulation in affecting health and disease outcomes
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