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. He...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-01-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1010581 |
| _version_ | 1797777395845955584 |
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| author | Lorenzo Lones Aaron DiAntonio |
| author_facet | Lorenzo Lones Aaron DiAntonio |
| author_sort | Lorenzo Lones |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-12T23:03:25Z |
| format | Article |
| id | doaj.art-1607439a023d4509a337445eee592f88 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-03-12T23:03:25Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-1607439a023d4509a337445eee592f882023-07-19T05:31:32ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042023-01-01191e101058110.1371/journal.pgen.1010581SIK3 and Wnk converge on Fray to regulate glial K+ buffering and seizure susceptibility.Lorenzo LonesAaron DiAntonioGlial 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.https://doi.org/10.1371/journal.pgen.1010581 |
| spellingShingle | Lorenzo Lones Aaron DiAntonio SIK3 and Wnk converge on Fray to regulate glial K+ buffering and seizure susceptibility. PLoS Genetics |
| 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 |
| url | https://doi.org/10.1371/journal.pgen.1010581 |
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