dc.contributor.author | Friedel, P | |
dc.contributor.author | Kahle, KT | |
dc.contributor.author | Zhang, J | |
dc.contributor.author | Hertz, N | |
dc.contributor.author | Pisella, LI | |
dc.contributor.author | Buhler, E | |
dc.contributor.author | Schaller, F | |
dc.contributor.author | Duan, J | |
dc.contributor.author | Khanna, AR | |
dc.contributor.author | Bishop, PN | |
dc.contributor.author | Shokat, KM | |
dc.contributor.author | Medina, I | |
dc.date.accessioned | 2018-07-05T16:45:43Z | |
dc.date.issued | 2015-06-30 | |
dc.description.abstract | Activation of Cl(-)-permeable γ-aminobutyric acid type A (GABAA) receptors elicits synaptic inhibition in mature neurons but excitation in immature neurons. This developmental "switch" in the GABA function depends on a postnatal decrease in intraneuronal Cl(-) concentration mediated by KCC2, a Cl(-)-extruding K(+)-Cl(-) cotransporter. We showed that the serine-threonine kinase WNK1 [with no lysine (K)] forms a physical complex with KCC2 in the developing mouse brain. Dominant-negative mutation, genetic depletion, or chemical inhibition of WNK1 in immature neurons triggered a hyperpolarizing shift in GABA activity by enhancing KCC2-mediated Cl(-) extrusion. This increase in KCC2 activity resulted from reduced inhibitory phosphorylation of KCC2 at two C-terminal threonines, Thr(906) and Thr(1007). Phosphorylation of both Thr(906) and Thr(1007) was increased in immature versus mature neurons. Together, these data provide insight into the mechanism regulating Cl(-) homeostasis in immature neurons, and suggest that WNK1-regulated changes in KCC2 phosphorylation contribute to the developmental excitatory-to-inhibitory GABA sequence. | en_GB |
dc.description.sponsorship | This work was supported by an ANR grant (French national research council) attributed to I.M.; an Inserm CR-PACA-FEDER grant to P.F.; and a Harvard-MIT Award in Neuroscience Grant. | en_GB |
dc.identifier.citation | Vol. 8, Issue 383, pp. ra65. | en_GB |
dc.identifier.doi | 10.1126/scisignal.aaa0354 | |
dc.identifier.uri | http://hdl.handle.net/10871/33380 | |
dc.language.iso | en | en_GB |
dc.publisher | American Association for the Advancement of Science | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/26126716 | en_GB |
dc.rights | Copyright © 2015, American Association for the Advancement of Science. | en_GB |
dc.subject | Animals | en_GB |
dc.subject | Embryo, Mammalian | en_GB |
dc.subject | Humans | en_GB |
dc.subject | Intracellular Signaling Peptides and Proteins | en_GB |
dc.subject | Membrane Potentials | en_GB |
dc.subject | Mice | en_GB |
dc.subject | Minor Histocompatibility Antigens | en_GB |
dc.subject | Neurons | en_GB |
dc.subject | PC12 Cells | en_GB |
dc.subject | Phosphorylation | en_GB |
dc.subject | Protein-Serine-Threonine Kinases | en_GB |
dc.subject | Rats | en_GB |
dc.subject | Symporters | en_GB |
dc.subject | WNK Lysine-Deficient Protein Kinase 1 | en_GB |
dc.subject | gamma-Aminobutyric Acid | en_GB |
dc.title | WNK1-regulated inhibitory phosphorylation of the KCC2 cotransporter maintains the depolarizing action of GABA in immature neurons. | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2018-07-05T16:45:43Z | |
dc.identifier.issn | 1945-0877 | |
exeter.place-of-publication | United States | en_GB |
dc.description | This is the author accepted manuscript. The final version is available from American Association for the Advancement of Science via the DOI in this record. | en_GB |
dc.identifier.journal | Science Signaling | en_GB |