{
  "abstract": "Seizures upregulate Na + -K + -2Cl - (NKCC1)-mediated Cl − influx and downregulate K + -Cl - (KCC2)-mediated Cl - efflux via the WNK-SPAK/OSR1 kinases, leading to cytoplasmic chloride ([Cl - ] i ) accumulation, reduced GABAergic inhibition and anticonvulsant failure. Early studies found that inhibiting WNK-kinase reduced baseline [Cl - ] i (E Cl ) and seizures via increased KCC2 activity. However, increased KCC2 activity alone should not affect E Cl whose determinants are more complex. We determined the net effects of WNK-SPAK/OSR1 pathway inhibitor WNK463 on E Cl and [Cl - ] i transients during spontaneous ictal-like discharges (ILDs). We found that WNK463 reduced interictal [Cl - ] i but did not change baseline [Cl - ] i measured in the presence of TTX. WNK463 enhanced neuronal Cl - extrusion during and after ILDs, before abolishing ILDs. Pharmacological inhibition and targeted siRNA silencing demonstrated that the anti-ictal effects of WNK463 involved both NKCC1 and KCC2. Our data support a mechanism whereby mutual NKCC1 inhibition and KCC2 activation via the WNK-SPAK/OSR1 pathway exert powerful anti-ictal effects by facilitating [Cl - ] i extrusion during ILDs.",
  "abstract_shown": true,
  "affiliations": [
    "Massachusetts General Hospital"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "V. I. Dzhala"
    },
    {
      "name": "F. H. Shiu"
    },
    {
      "name": "N. Rahmati"
    },
    {
      "name": "A. Carroll"
    },
    {
      "name": "R. Bae"
    },
    {
      "name": "K. T. Kahle"
    },
    {
      "name": "K. Staley"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7hvgbwzytxkmj.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.06.10.731153",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.06.10.731153v2.full",
  "id": "7hvgbwzytxkmj",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.06.10.731153v2",
  "language": null,
  "licence": "PDM-1.0",
  "licence_label": "Public domain",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/publicdomain/mark/1.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "2738|Epilepsy research and treatment"
    ]
  ],
  "openalex": "W7164513343",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.06.10.731153v2.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-06-10",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/7hvgbwzytxkmj.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:49Z",
      "native_id": "10.64898/2026.06.10.731153",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.06.10.731153v3"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "WNK-SPAK/OSR1 signaling pathway facilitates ictal activity via reduced neuronal chloride extrusion rate",
  "title_text": "WNK-SPAK/OSR1 signaling pathway facilitates ictal activity via reduced neuronal chloride extrusion rate",
  "type": "preprint",
  "updated_at": "2026-10-30T12:22:26Z",
  "url": "https://research.draconitic.com/paper/7hvgbwzytxkmj",
  "venue": "bioRxiv",
  "versions": []
}