Development and regulation of chloride homeostasis in the central nervous system.
Development and regulation of chloride homeostasis in the central nervous system.
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DOI：
10.3389/fncel.2015.00371
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发表时间：
2015
影响因子：
5.3
通讯作者：
Fukuda A
中科院分区：
文献类型：
--
作者：
Watanabe M;Fukuda A
γ-氨基丁酸（GABA）是成熟中枢神经系统（CNS）的主要抑制性神经递质。GABA能传递从兴奋到抑制的发育转换是由Cl−梯度的变化诱导的，Cl −梯度是由阳离子-Cl −共转运蛋白产生的。Na+-K+-2Cl−协同转运蛋白（NKCC 1）的Cl−蓄积增加了细胞内Cl−浓度（[Cl−]i），使得GABA使神经元前体和未成熟神经元去极化。随后的个体发育开关，即，Cl−-挤出器KCC 2（一种神经元特异性K+-Cl−共转运蛋白）的上调，伴或不伴NKCC 1的下调，导致成熟神经元中[Cl−]i水平降低和GABA的超极化作用。Cl−稳态的发展取决于NKCC 1和KCC 2表达的发育变化。一般来说，[Cl−]i的发育变化（减少）与神经系统的成熟平行，例如，最早在脊髓、下丘脑和丘脑，然后是边缘系统，最后在新皮层。存在几种KCC 2和/或NKCC 1表达的调节剂，包括脑源性神经营养因子（BDNF）、胰岛素样生长因子（IGF）和囊性纤维化跨膜传导调节剂（CFTR）。因此，这些调节因子的区域性差异表达也可能导致Cl−稳态的区域性发展变化。KCC 2和NKCC 1的功能也受PKC、Src家族酪氨酸激酶和WNK 1 -4及其下游效应物STE 20/SPS 1相关的脯氨酸/丙氨酸富集激酶（SPAK）-氧化应激反应激酶-1（OSR 1）的磷酸化调节。此外，这些激酶的激活受体液因子如雌激素和牛磺酸的调节。由于这些转运蛋白使用Na+和K+离子的电化学驱动力，因此与Na+-K+ ATP酶及其调节剂（如肌酸激酶（CK））的拓扑相互作用应调节Cl−转运蛋白的功能。因此，这些Cl−转运体调节因子和调节因子的区域发育调节也可能在Cl−稳态的发展中发挥关键作用。
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the mature central nervous system (CNS). The developmental switch of GABAergic transmission from excitation to inhibition is induced by changes in Cl− gradients, which are generated by cation-Cl− co-transporters. An accumulation of Cl− by the Na+-K+-2Cl− co-transporter (NKCC1) increases the intracellular Cl− concentration ([Cl−]i) such that GABA depolarizes neuronal precursors and immature neurons. The subsequent ontogenetic switch, i.e., upregulation of the Cl−-extruder KCC2, which is a neuron-specific K+-Cl− co-transporter, with or without downregulation of NKCC1, results in low [Cl−]i levels and the hyperpolarizing action of GABA in mature neurons. Development of Cl− homeostasis depends on developmental changes in NKCC1 and KCC2 expression. Generally, developmental shifts (decreases) in [Cl−]i parallel the maturation of the nervous system, e.g., early in the spinal cord, hypothalamus and thalamus, followed by the limbic system, and last in the neocortex. There are several regulators of KCC2 and/or NKCC1 expression, including brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF), and cystic fibrosis transmembrane conductance regulator (CFTR). Therefore, regionally different expression of these regulators may also contribute to the regional developmental shifts of Cl− homeostasis. KCC2 and NKCC1 functions are also regulated by phosphorylation by enzymes such as PKC, Src-family tyrosine kinases, and WNK1–4 and their downstream effectors STE20/SPS1-related proline/alanine-rich kinase (SPAK)-oxidative stress responsive kinase-1 (OSR1). In addition, activation of these kinases is modulated by humoral factors such as estrogen and taurine. Because these transporters use the electrochemical driving force of Na+ and K+ ions, topographical interaction with the Na+-K+ ATPase and its modulators such as creatine kinase (CK) should modulate functions of Cl− transporters. Therefore, regional developmental regulation of these regulators and modulators of Cl− transporters may also play a pivotal role in the development of Cl− homeostasis.