{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:04:37Z","timestamp":1791201877947,"version":"4.2.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Chloride homeostasis, and thereby the efficacy of chloride-permeable GABAA receptor signaling, depends on the dynamic balance between NKCC1 (Na+\u2013K+\u20132Cl\u2212 cotransporter 1) and KCC2 (K+\u2013Cl\u2212 cotransporter 2), which respectively mediate chloride influx and extrusion to tightly control intracellular chloride concentration ([Cl\u2212]i).<\/jats:p>\n                  <jats:p>Here, we uncover an unexpected mechanism by which NKCC1 regulates KCC2 membrane stability and function. Co-immunoprecipitation experiments from mouse brain lysates revealed that KCC2 associates with NKCC1 and SPAK (STE20\/SPS1-related proline-alanine-rich kinase), indicating that these proteins are within a common molecular interaction network. Furthermore, we show that NKCC1 and KCC2 form co-clusters in the plasma membrane of hippocampal neurons and that freely diffusing KCC2 molecules become trapped within NKCC1 membrane clusters.<\/jats:p>\n                  <jats:p>These observations suggest that NKCC1 coordinates SPAK- and PP1-dependent regulation of KCC2. Guided by molecular modeling, we designed peptides targeting specific interactions within this complex. Peptides that activate SPAK by engaging NKCC1\u2019s PP1-binding motif decrease KCC2 surface expression and impair chloride extrusion, whereas a SPAK-inhibiting peptide that prevents SPAK recruitment to NKCC1, stabilizes KCC2 in membrane clusters, and enhances chloride extrusion.<\/jats:p>\n                  <jats:p>An optimized peptide analog suitable for in vivo use preserves KCC2 clustering under hyperexcitable conditions, reduces seizure frequency and severity in an acute pentylenetetrazol-induced (PTZ) seizure model, and suppresses ictal activity in chronically epileptic human tissue.<\/jats:p>\n                  <jats:p>Together, these findings identify NKCC1 as a key regulator of KCC2 membrane stability, reveal NKCC1-KCC2 coupling as a critical determinant of inhibitory signaling, and establish this complex as a potential therapeutic target for restoring chloride homeostasis in epilepsy and related neurological disorders.<\/jats:p>","DOI":"10.1093\/brain\/awag341","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T11:42:00Z","timestamp":1790941320000},"source":"Crossref","is-referenced-by-count":0,"title":["NKCC1 coordinates SPAK\u2013PP1 signalling to regulate KCC2 membrane stability and seizure susceptibility"],"prefix":"10.1093","author":[{"given":"Erwan","family":"Pol","sequence":"first","affiliation":[{"name":"ESPCI, CNRS UMR 8249, PSL Universit\u00e9 , 75005 Paris ,","place":["France"]},{"name":"INSERM UMR-S 1270, Sorbonne Universit\u00e9, Institut du Fer \u00e0 Moulin , 75005 Paris ,","place":["France"]},{"name":"Sorbonne Universit\u00e9, CNRS, Inserm, Center of Neuroscience Neuro-SU , 75005 Paris ,","place":["France"]},{"name":"Sorbonne Universit\u00e9, CNRS, Inserm, Institut de Biologie Paris-Seine , IBPS, 75005 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9lia","family":"Delhaye","sequence":"additional","affiliation":[{"name":"ESPCI, CNRS UMR 8249, PSL Universit\u00e9 , 75005 Paris ,","place":["France"]},{"name":"INSERM UMR-S 1270, Sorbonne Universit\u00e9, Institut du Fer \u00e0 Moulin , 75005 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Cases-Cunillera","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Neuronal and Astroglial Signaling in Epilepsy and Glioma , 75014 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizaveta","family":"Boiko","sequence":"additional","affiliation":[{"name":"Neuroscience Centre, HiLife, University of Helsinki , Helsinki ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Russeau","sequence":"additional","affiliation":[{"name":"ESPCI, CNRS UMR 8249, PSL Universit\u00e9 , 75005 Paris ,","place":["France"]},{"name":"INSERM UMR-S 1270, Sorbonne Universit\u00e9, Institut du Fer \u00e0 Moulin , 75005 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nalia","family":"Samba","sequence":"additional","affiliation":[{"name":"ESPCI, CNRS UMR 8249, PSL Universit\u00e9 , 75005 Paris ,","place":["France"]},{"name":"INSERM UMR-S 1270, Sorbonne Universit\u00e9, Institut du Fer \u00e0 Moulin , 75005 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin","family":"Pillon","sequence":"additional","affiliation":[{"name":"ESPCI, CNRS UMR 8249, PSL Universit\u00e9 , 75005 Paris ,","place":["France"]},{"name":"INSERM UMR-S 1270, Sorbonne Universit\u00e9, Institut du Fer \u00e0 Moulin , 75005 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Blachier","sequence":"additional","affiliation":[{"name":"ESPCI, CNRS UMR 8249, PSL Universit\u00e9 , 75005 Paris ,","place":["France"]},{"name":"INSERM UMR-S 1270, Sorbonne Universit\u00e9, Institut du Fer \u00e0 Moulin , 75005 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrien","family":"Bouchet","sequence":"additional","affiliation":[{"name":"ESPCI, CNRS UMR 8249, PSL Universit\u00e9 , 75005 Paris ,","place":["France"]},{"name":"INSERM UMR-S 1270, Sorbonne Universit\u00e9, Institut du Fer \u00e0 Moulin , 75005 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Piesse","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, CNRS, Inserm, Center of Neuroscience Neuro-SU , 75005 Paris ,","place":["France"]},{"name":"Sorbonne Universit\u00e9, CNRS, Inserm, Institut de Biologie Paris-Seine , IBPS, 75005 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coralie","family":"Di Scala","sequence":"additional","affiliation":[{"name":"Neuroscience Centre, HiLife, University of Helsinki , Helsinki ,","place":["Finland"]},{"name":"INMED, INSERM, Aix Marseille universit\u00e9 , Marseille ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Pallud","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, GHU Paris Psychiatry and Neurosciences, Sainte-Anne Hospital , 75014 Paris ,","place":["France"]},{"name":"Institute of Psychiatry and Neuroscience of Paris, University Paris Cit\u00e9 , INSERM U1266, IMABRAIN, 75014 Paris ,","place":["France"]},{"name":"Universit\u00e9 Paris Cit\u00e9 , 75005 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Huberfeld","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Neuronal and Astroglial Signaling in Epilepsy and Glioma , 75014 Paris ,","place":["France"]},{"name":"Department of Neurology, Hopital Fondation Adolphe de Rothschild , 75019 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Pietrancosta","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, CNRS, Inserm, Center of Neuroscience Neuro-SU , 75005 Paris ,","place":["France"]},{"name":"Sorbonne Universit\u00e9, CNRS, Inserm, Institut de Biologie Paris-Seine , IBPS, 75005 Paris ,","place":["France"]},{"name":"Sorbonne Universit\u00e9, \u00c9cole Normale Sup\u00e9rieure, Universit\u00e9 PSL, CNRS, Chimie Physique et Chimie du Vivant (CPCV), \u00a0 75005 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"L\u00e9vi","sequence":"additional","affiliation":[{"name":"ESPCI, CNRS UMR 8249, PSL Universit\u00e9 , 75005 Paris ,","place":["France"]},{"name":"INSERM UMR-S 1270, Sorbonne Universit\u00e9, Institut du Fer \u00e0 Moulin , 75005 Paris 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