SIK3 and Wnk converge on Fray to regulate glial K+ buffering and seizure susceptibility

PLoS Genet. 2023 Jan 10;19(1):e1010581. doi: 10.1371/journal.pgen.1010581. eCollection 2023 Jan.


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.

MeSH terms

  • Animals
  • Drosophila / metabolism
  • Drosophila Proteins* / genetics
  • Neuroglia / metabolism
  • Neurons / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Seizures / genetics
  • Sodium-Potassium-Chloride Symporters / metabolism


  • Drosophila Proteins
  • Sodium-Potassium-Chloride Symporters
  • WNK protein, Drosophila
  • Protein Serine-Threonine Kinases
  • fray protein, Drosophila