INSERM UMR-S 1270, Institut du Fer à Moulin, Sorbonne Université, 75005 Paris, France.
Cells. 2023 Jan 31;12(3):464. doi: 10.3390/cells12030464.
An upregulation of the Na-K-2Cl cotransporter NKCC1, the main chloride importer in mature neurons, can lead to depolarizing/excitatory responses mediated by GABA type A receptors (GABARs) and, thus, to hyperactivity. Understanding the regulatory mechanisms of NKCC1 would help prevent intra-neuronal chloride accumulation that occurs in pathologies with defective inhibition. The cell mechanisms regulating NKCC1 are poorly understood. Here, we report in mature hippocampal neurons that GABAergic activity controls the membrane diffusion and clustering of NKCC1 via the chloride-sensitive WNK lysine deficient protein kinase 1 (WNK1) and the downstream Ste20 Pro-line Asparagine Rich Kinase (SPAK) kinase that directly phosphorylates NKCC1 on key threonine residues. At rest, this signaling pathway has little effect on intracellular Cl concentration, but it participates in the elevation of intraneuronal Cl concentration in hyperactivity conditions associated with an up-regulation of NKCC1. The fact that the main chloride exporter, the K-Cl cotransporter KCC2, is also regulated in mature neurons by the WNK1 pathway indicates that this pathway will be a target of choice in the pathology.
钠钾-2 氯共转运体 NKCC1 的上调，是成熟神经元中主要的氯离子内流，可导致 GABA 型 A 受体 (GABARs) 介导的去极化/兴奋反应，从而导致过度活跃。了解 NKCC1 的调节机制有助于防止抑制功能缺陷的病理过程中发生的神经元内氯离子积累。NKCC1 的细胞调节机制尚不清楚。在这里，我们报告在成熟的海马神经元中，GABA 能活性通过氯离子敏感的丝氨酸苏氨酸激酶激酶 1（WNK1）和下游的丝裂原活化蛋白激酶激酶 Ste20 脯氨酸天冬氨酸富含激酶（SPAK）控制 NKCC1 的膜扩散和聚集，WNK1 可直接在 NKCC1 的关键苏氨酸残基上磷酸化。在静息状态下，该信号通路对细胞内 Cl-浓度几乎没有影响，但它参与了与 NKCC1 上调相关的过度活跃状态下细胞内 Cl-浓度的升高。事实上，主要的氯离子外排体，K-Cl 共转运体 KCC2，也被 WNK1 途径在成熟神经元中调节，这表明该途径将成为病理中的首选目标。
