Research advances on CaMKs-mediated neurodevelopmental injury

IF 4.8 2区 医学 Q1 TOXICOLOGY
Lingxu Kong, Jing Yang, Huajie Yang, Bin Xu, Tianyao Yang, Wei Liu
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引用次数: 0

Abstract

Calcium/calmodulin-dependent protein kinases (CaMKs) are important proteins in the calcium signaling cascade response pathway, which can broadly regulate biological functions in vivo. Multifunctional CaMKs play key roles in neural development, including neuronal circuit building, synaptic plasticity establishment, and neurotrophic factor secretion. Currently, four familial proteins, calcium/calmodulin-dependent protein kinase I (CaMKI), calcium/calmodulin-dependent protein kinase II (CaMKII), eukaryotic elongation factor 2 kinase (eEF2K, popularly known as CaMKIII) and calcium/calmodulin-dependent protein kinase IV (CaMKIV), are thought to have been the most extensively studied during neurodevelopment. Although their spatial structures are extremely similar, as well as the initial starting point of activation, both require the activation of calcium and calmodulin (CaM) complexes to be involved in the process, and the phosphorylation sites and modes of each member are different. Furthermore, due to the high structural similarity of CaMKs, their members may play synergistic roles in the regulation of neural development, but different CaMKs also have their own means of regulating neural development. In this review, we first describe the visualized protein structural forms of CaMKI, CaMKII, eEF2K and CaMKIV, and then describe the functions of each kinase in neurodevelopment. After that, we focus on four main mechanisms of neurodevelopmental damage caused by CaMKs: CaMKI/ERK/CREB pathway inhibition leading to dendritic spine structural damage; Ca2+/CaM/CaMKII through induction of mitochondrial kinetic disorders leading to neurodevelopmental damage; CaMKIII/eEF2 hyperphosphorylation affects the establishment of synaptic plasticity; and CaMKIV/JNK/NF-κB through induction of an inflammatory response leading to neurodevelopmental damage. In conclusion, we briefly discuss the pathophysiological significance of aberrant CaMK family expression in neurodevelopmental disorders, as well as the protective effects of conventional CaMKII and CaMKIII antagonists against neurodevelopmental injury.

Abstract Image

有关 CaMKs 介导的神经发育损伤的研究进展
钙/钙调蛋白依赖性蛋白激酶(CaMKs)是钙信号级联反应途径中的重要蛋白,可广泛调控体内生物功能。多功能 CaMKs 在神经发育过程中发挥着关键作用,包括神经元回路构建、突触可塑性建立和神经营养因子分泌。目前,人们认为在神经发育过程中对钙/钙调蛋白依赖性蛋白激酶 I(CaMKI)、钙/钙调蛋白依赖性蛋白激酶 II(CaMKII)、真核延伸因子 2 激酶(eEF2K,俗称 CaMKIII)和钙/钙调蛋白依赖性蛋白激酶 IV(CaMKIV)这四种家族蛋白的研究最为广泛。虽然它们的空间结构以及激活的初始起点极为相似,但都需要钙和钙调素(CaM)复合物的激活才能参与这一过程,而且每个成员的磷酸化位点和模式也不尽相同。此外,由于 CaMK 的结构高度相似,其成员可能在神经发育调控中发挥协同作用,但不同的 CaMK 也有各自的神经发育调控手段。在这篇综述中,我们首先描述了 CaMKI、CaMKII、eEF2K 和 CaMKIV 的可视化蛋白结构形式,然后描述了每种激酶在神经发育中的功能。之后,我们将重点介绍 CaMKs 造成神经发育损伤的四种主要机制:CaMKI/ERK/CREB通路抑制导致树突棘结构损伤;Ca2+/CaM/CaMKII通过诱导线粒体动力学紊乱导致神经发育损伤;CaMKIII/eEF2过度磷酸化影响突触可塑性的建立;CaMKIV/JNK/NF-κB通过诱导炎症反应导致神经发育损伤。最后,我们简要讨论了神经发育障碍中 CaMK 家族表达异常的病理生理学意义,以及传统 CaMKII 和 CaMKIII 拮抗剂对神经发育损伤的保护作用。
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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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