Developmentally regulated KCC2 phosphorylation is essential for dynamic GABA-mediated inhibition and survival
In: Science signaling, Jg. 12 (2019-10-17), Heft 603
Online
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Zugriff:
Despite its importance for γ-aminobutyric acid (GABA) inhibition and involvement in neurodevelopmental disease, the regulatory mechanisms of the K(+)/Cl(−) co-transporter 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 Thr(906) and Thr(1007), which inhibits KCC2 activity, underwent dephosphorylation in parallel with the GABA excitatory-inhibitory sequence in vivo. Knock-in mice expressing the homozygous phospho-mimetic KCC2 mutations T906E/T1007E (Kcc2(E/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. Kcc2(E/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.
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Developmentally regulated KCC2 phosphorylation is essential for dynamic GABA-mediated inhibition and survival
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Autor/in / Beteiligte Person: | Alper, Seth L. ; M. Shahid Mansuri ; Duan, Jingjing ; Lifton, Richard P. ; Watanabe, Miho ; Karimy, Jason K. ; Delpire, Eric ; Fukuda, Atsuo ; Kahle, Kristopher T. ; Zhang, Jinwei |
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Zeitschrift: | Science signaling, Jg. 12 (2019-10-17), Heft 603 |
Veröffentlichung: | 2019 |
Medientyp: | unknown |
ISSN: | 1937-9145 (print) |
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