Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 25, Pages 20839-20850Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.319418
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology, Japan [2002195, 21026013, 23123505]
- Japan Society for the Promotion of Science [19390058, 23500387]
- Kanzawa Medical Research Foundation
- Salt Science Research Foundation [1125]
- Grants-in-Aid for Scientific Research [23500387, 21026013, 23590276, 23123505, 19390058] Funding Source: KAKEN
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GABA inhibits mature neurons and conversely excites immature neurons due to lower K+-Cl- cotransporter 2 (KCC2) expression. We observed that ectopically expressed KCC2 in embryonic cerebral cortices was not active; however, KCC2 functioned in newborns. In vitro studies revealed that taurine increased KCC2 inactivation in a phosphorylation-dependent manner. When Thr-906 and Thr-1007 residues in KCC2 were substituted with Ala (KCC2T906A/T1007A), KCC2 activity was facilitated, and the inhibitory effect of taurine was not observed. Exogenous taurine activated the with-no-lysine protein kinase 1 (WNK1) and downstream STE20/SPS1-related proline/alanine-rich kinase (SPAK)/oxidative stress response 1 (OSR1), and overexpression of active WNK1 resulted in KCC2 inhibition in the absence of taurine. Phosphorylation of SPAK was consistently higher in embryonic brains compared with that of neonatal brains and down-regulated by a taurine transporter inhibitor in vivo. Furthermore, cerebral radial migration was perturbed by a taurine-insensitive form of KCC2, KCC2T906A/T1007A, which may be regulated by WNK-SPAK/OSR1 signaling. Thus, taurine and WNK-SPAK/OSR1 signaling may contribute to embryonic neuronal Cl- homeostasis, which is required for normal brain development.
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