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Developmentally regulated KCC2 phosphorylation is essential for dynamic GABA-mediated inhibition and survival.
Science Signaling ( IF 7.3 ) Pub Date : 2019-10-15 , DOI: 10.1126/scisignal.aaw9315
Miho Watanabe 1 , Jinwei Zhang 2 , M Shahid Mansuri 3 , Jingjing Duan 4 , Jason K Karimy 3 , Eric Delpire 5 , Seth L Alper 6, 7 , Richard P Lifton 8, 9 , Atsuo Fukuda 1, 10 , Kristopher T Kahle 11
Affiliation  

Despite its importance for γ-aminobutyric acid (GABA) inhibition and involvement in neurodevelopmental disease, the regulatory mechanisms of the K+/Cl- cotransporter KCC2 (encoded by SLC12A5) during maturation of the central nervous system (CNS) are not entirely understood. Here, we applied quantitative phosphoproteomics to systematically map sites of KCC2 phosphorylation during CNS development in the mouse. KCC2 phosphorylation at Thr906 and Thr1007, which inhibits KCC2 activity, underwent dephosphorylation in parallel with the GABA excitatory-inhibitory sequence in vivo. Knockin mice expressing the homozygous phosphomimetic KCC2 mutations T906E/T1007E (Kcc2E/E ), which prevented the normal developmentally regulated dephosphorylation of these sites, exhibited early postnatal death from respiratory arrest and a marked absence of cervical spinal neuron respiratory discharges. Kcc2E/E mice also displayed disrupted lumbar spinal neuron locomotor rhythmogenesis and touch-evoked status epilepticus associated with markedly impaired KCC2-dependent Cl- extrusion. These data identify a previously unknown phosphorylation-dependent KCC2 regulatory mechanism during CNS development that is essential for dynamic GABA-mediated inhibition and survival.

中文翻译:

发育受调节的KCC2磷酸化对于动态GABA介导的抑制和存活至关重要。

尽管它对于抑制γ-氨基丁酸(GABA)并参与神经发育疾病具有重要意义,但在中枢神经系统(CNS)成熟过程中K + / Cl-共转运蛋白KCC2(由SLC12A5编码)的调节机制尚未完全了解。在这里,我们应用定量磷酸化蛋白质组学来系统地绘制小鼠中枢神经系统发育过程中KCC2磷酸化的位点。抑制KCC2活性的Thr906和Thr1007处的KCC2磷酸化与体内的GABA兴奋性抑制序列平行进行了去磷酸化。表达纯合拟磷酸酶KCC2突变T906E / T1007E(Kcc2E / E)的敲除小鼠,这些突变阻止了这些位点的正常发育调控的去磷酸化,表现出因呼吸骤停而出生后的早期死亡,并且明显缺乏颈脊髓神经元呼吸放电。Kcc2​​E / E小鼠还显示出与明显受损的KCC2依赖性Cl-挤出有关的腰椎神经元运动节律紊乱和触摸诱发的癫痫持续状态。这些数据确定了CNS发育过程中以前未知的磷酸化依赖性KCC2调控机制,这对于动态GABA介导的抑制和存活至关重要。
更新日期:2019-10-16
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