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SIK3 and Wnk converge on Fray to regulate glial K(+) buffering and seizure susceptibility
Glial cells play a critical role in maintaining homeostatic ion concentration gradients. Salt-inducible kinase 3 (SIK3) regulates a gene expression program that controls K(+) buffering in glia, and upregulation of this pathway suppresses seizure behavior in the eag, Shaker hyperexcitability mutant....
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870106/ https://www.ncbi.nlm.nih.gov/pubmed/36626385 http://dx.doi.org/10.1371/journal.pgen.1010581 |
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author | Lones, Lorenzo DiAntonio, Aaron |
author_facet | Lones, Lorenzo DiAntonio, Aaron |
author_sort | Lones, Lorenzo |
collection | PubMed |
description | Glial cells play a critical role in maintaining homeostatic ion concentration gradients. Salt-inducible kinase 3 (SIK3) regulates a gene expression program that controls K(+) buffering in glia, and upregulation of this pathway suppresses seizure behavior in the eag, Shaker hyperexcitability mutant. Here we show that boosting the glial SIK3 K(+) buffering pathway suppresses seizures in three additional molecularly diverse hyperexcitable mutants, highlighting the therapeutic potential of upregulating glial K(+) buffering. We then explore additional mechanisms regulating glial K(+) buffering. Fray, a transcriptional target of the SIK3 K(+) buffering program, is a kinase that promotes K(+) uptake by activating the Na(+)/K(+)/Cl(-) co-transporter, Ncc69. We show that the Wnk kinase phosphorylates Fray in Drosophila glia and that this activity is required to promote K(+) buffering. This identifies Fray as a convergence point between the SIK3-dependent transcriptional program and Wnk-dependent post-translational regulation. Bypassing both regulatory mechanisms via overexpression of a constitutively active Fray in glia is sufficient to robustly suppress seizure behavior in multiple Drosophila models of hyperexcitability. Finally, we identify cortex glia as a critical cell type for regulation of seizure susceptibility, as boosting K(+) buffering via expression of activated Fray exclusively in these cells is sufficient to suppress seizure behavior. These findings highlight Fray as a key convergence point for distinct K(+) buffering regulatory mechanisms and cortex glia as an important locus for control of neuronal excitability. |
format | Online Article Text |
id | pubmed-9870106 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-98701062023-01-24 SIK3 and Wnk converge on Fray to regulate glial K(+) buffering and seizure susceptibility Lones, Lorenzo DiAntonio, Aaron PLoS Genet Research Article Glial cells play a critical role in maintaining homeostatic ion concentration gradients. Salt-inducible kinase 3 (SIK3) regulates a gene expression program that controls K(+) buffering in glia, and upregulation of this pathway suppresses seizure behavior in the eag, Shaker hyperexcitability mutant. Here we show that boosting the glial SIK3 K(+) buffering pathway suppresses seizures in three additional molecularly diverse hyperexcitable mutants, highlighting the therapeutic potential of upregulating glial K(+) buffering. We then explore additional mechanisms regulating glial K(+) buffering. Fray, a transcriptional target of the SIK3 K(+) buffering program, is a kinase that promotes K(+) uptake by activating the Na(+)/K(+)/Cl(-) co-transporter, Ncc69. We show that the Wnk kinase phosphorylates Fray in Drosophila glia and that this activity is required to promote K(+) buffering. This identifies Fray as a convergence point between the SIK3-dependent transcriptional program and Wnk-dependent post-translational regulation. Bypassing both regulatory mechanisms via overexpression of a constitutively active Fray in glia is sufficient to robustly suppress seizure behavior in multiple Drosophila models of hyperexcitability. Finally, we identify cortex glia as a critical cell type for regulation of seizure susceptibility, as boosting K(+) buffering via expression of activated Fray exclusively in these cells is sufficient to suppress seizure behavior. These findings highlight Fray as a key convergence point for distinct K(+) buffering regulatory mechanisms and cortex glia as an important locus for control of neuronal excitability. Public Library of Science 2023-01-10 /pmc/articles/PMC9870106/ /pubmed/36626385 http://dx.doi.org/10.1371/journal.pgen.1010581 Text en © 2023 Lones, DiAntonio https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Lones, Lorenzo DiAntonio, Aaron SIK3 and Wnk converge on Fray to regulate glial K(+) buffering and seizure susceptibility |
title | SIK3 and Wnk converge on Fray to regulate glial K(+) buffering and seizure susceptibility |
title_full | SIK3 and Wnk converge on Fray to regulate glial K(+) buffering and seizure susceptibility |
title_fullStr | SIK3 and Wnk converge on Fray to regulate glial K(+) buffering and seizure susceptibility |
title_full_unstemmed | SIK3 and Wnk converge on Fray to regulate glial K(+) buffering and seizure susceptibility |
title_short | SIK3 and Wnk converge on Fray to regulate glial K(+) buffering and seizure susceptibility |
title_sort | sik3 and wnk converge on fray to regulate glial k(+) buffering and seizure susceptibility |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9870106/ https://www.ncbi.nlm.nih.gov/pubmed/36626385 http://dx.doi.org/10.1371/journal.pgen.1010581 |
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