title: Taurine inhibits K+-Cl- cotransporter KCC2 to regulate embryonic Cl- homeostasis via with-no-lysine (WNK) protein kinase signaling pathway.
abstract: 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.
authors.affiliation: Department of Physiology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan. ino-k@umin.ac.jp
authors.forename: Koichi
authors.initials: K
authors.lastname: Inoue
authors.forename: Tomonori
authors.initials: T
authors.lastname: Furukawa
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kumada
authors.forename: Junko
authors.initials: J
authors.lastname: Yamada
authors.forename: Tianying
authors.initials: T
authors.lastname: Wang
authors.forename: Rieko
authors.initials: R
authors.lastname: Inoue
authors.forename: Atsuo
authors.initials: A
authors.lastname: Fukuda
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D015778:Minor Histocompatibility Antigens; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D013654:Taurine / Q000494:pharmacology*; D000076204:WNK Lysine-Deficient Protein Kinase 1; D000096922:K Cl- Cotransporters
chemical_list: D015778:Minor Histocompatibility Antigens; D009419:Nerve Tissue Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D027981:Symporters; D013654:Taurine; D000076204:WNK Lysine-Deficient Protein Kinase 1; D000096922:K Cl- Cotransporters; C116037:PAS domain kinases; C506604:Oxsr1 protein, rat; C410410:Wnk1 protein, rat