Current view on the functional regulation of the neuronal K(+)-Cl(-) cotransporter KCC2.
Current view on the functional regulation of the neuronal K(+)-Cl(-) cotransporter KCC2.
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关于神经元K（+） - Cl（ - ）共转运蛋白KCC2功能调节的当前视图。
DOI：
10.3389/fncel.2014.00027
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发表时间：
2014
影响因子：
5.3
通讯作者：
Pellegrino C
中科院分区：
文献类型：
--
作者：
Medina I;Friedel P;Rivera C;Kahle KT;Kourdougli N;Uvarov P;Pellegrino C
在哺乳动物中枢神经系统(CNS)中，氯离子(ClGABAA)和甘氨酸受体(GABAAR和GlyR)穿透氯离子(ClGABAA)和甘氨酸受体(GlyR)的抑制强度依赖于细胞内的ClGABAA浓度([Cl−]i)。降低[Cl−]i可增强抑制作用，而升高[Cl−]i可促进神经元的活动。神经元的基础[Cl-−]i水平以及其[Cl-−]i的排出能力严重依赖于电子中和型K+-Cl−共转运体KCC2的活性，KCC2是SLC12型阳离子-氯−共转运体家族的成员。KCC2缺乏影响神经元的迁移、形成和GABA能和谷氨酸能突触连接的成熟，导致网络兴奋性和惊厥活动。包括多种癫痫亚型、神经病理性疼痛和精神分裂症在内的几种神经系统疾病，以及创伤和缺血等各种损伤，都与KCC2的氯离子−排出能力显著降低有关，从而导致[氯离子−]i增加，从而导致神经元网络的超兴奋性。因此，找出控制KCC2功能调节的关键上游分子介质，并用小分子修饰这些信号通路，可能构成一种治疗多种疾病的新的神经治疗策略。在这里，我们讨论了最近的进展，了解调节KCC2活性的机制，以及这些机制在神经元CL−动态平衡和GABA能神经传递中所起的作用。由于KCC2介导电子中和运输，其活性的实验记录构成了一个重要的研究挑战；因此，我们还概述了用于监测KCC2在生理和病理条件下的功能的不同方法。
In the mammalian central nervous system (CNS), the inhibitory strength of chloride (Cl−)-permeable GABAA and glycine receptors (GABAAR and GlyR) depends on the intracellular Cl− concentration ([Cl−]i). Lowering [Cl−]i enhances inhibition, whereas raising [Cl−]i facilitates neuronal activity. A neuron's basal level of [Cl−]i, as well as its Cl− extrusion capacity, is critically dependent on the activity of the electroneutral K+-Cl− cotransporter KCC2, a member of the SLC12 cation-Cl− cotransporter (CCC) family. KCC2 deficiency compromises neuronal migration, formation and the maturation of GABAergic and glutamatergic synaptic connections, and results in network hyperexcitability and seizure activity. Several neurological disorders including multiple epilepsy subtypes, neuropathic pain, and schizophrenia, as well as various insults such as trauma and ischemia, are associated with significant decreases in the Cl− extrusion capacity of KCC2 that result in increases of [Cl−]i and the subsequent hyperexcitability of neuronal networks. Accordingly, identifying the key upstream molecular mediators governing the functional regulation of KCC2, and modifying these signaling pathways with small molecules, might constitute a novel neurotherapeutic strategy for multiple diseases. Here, we discuss recent advances in the understanding of the mechanisms regulating KCC2 activity, and of the role these mechanisms play in neuronal Cl− homeostasis and GABAergic neurotransmission. As KCC2 mediates electroneutral transport, the experimental recording of its activity constitutes an important research challenge; we therefore also, provide an overview of the different methodological approaches utilized to monitor function of KCC2 in both physiological and pathological conditions.
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影响因子：
5.3
作者：
Chamma I;Chevy Q;Poncer JC;Lévi S
通讯作者：
Lévi S
影响因子：
--
作者：
Carmosino M;Rizzo F;Torretta S;Procino G;Svelto M
通讯作者：
Svelto M
DOI：
10.1523/jneurosci.5309-08.2009
发表时间：
2009-03-18
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bragin A;Azizyan A;Almajano J;Engel J Jr
通讯作者：
Engel J Jr
影响因子：
--
作者：
Berglund, Ken;Kuner, Thomas;Augustine, George J
通讯作者：
Augustine, George J
影响因子：
5.5
作者：
Banke, Tue G.;Gegelashvili, Georgi
通讯作者：
Gegelashvili, Georgi