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However, the exact mechanism has not yet been elucidated. Here, we explored the roles of <jats:bold>NEDD4-2<\/jats:bold> and the <jats:bold>CLC-2<\/jats:bold> channel in regulating neuronal excitability and mesial temporal lobe epilepsy (MTLE) pathogenesis. First, chronic MTLE models were induced by lithium-pilocarpine in developmental rats. Coimmunoprecipitation analysis revealed that the interaction between CLC-2 and <jats:bold>NEDD4-2<\/jats:bold>. Western blot analyses indicated that <jats:bold>NEDD4-2<\/jats:bold> expression was downregulated, while phosphorylated (P-) <jats:bold>NEDD4-2<\/jats:bold> and <jats:bold>CLC-2<\/jats:bold> expression was upregulated in adult MTLE rats. Then, the primary hippocampal neuronal cells were isolated and cultured, and the <jats:bold>NEDD4-2<\/jats:bold> was knocked down by shRNA vector, resulting in decreased protein levels of CLC-2. While CLC-2 absence caused increased <jats:bold>NEDD4-2<\/jats:bold> in cells. Next, in an epileptic cell model induced by a Mg<jats:sup>2+<\/jats:sup>-free culture, whole-cell current-clamp recording demonstrated that <jats:bold>NEDD4-2<\/jats:bold> deficiency inhibited the spontaneous action potentials of cells, and CLC-2 absence caused more significant decrease in the spontaneous action potentials of cells. In conclusion, we herein revealed that <jats:bold>NEDD4-2<\/jats:bold> regulates the expression of CLC-2, which is involved in neuronal excitability, and participates in the pathogenesis of MTLE.<\/jats:p>","DOI":"10.1038\/s41598-024-52399-4","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T06:02:37Z","timestamp":1709100157000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NEDD4-2 and the CLC-2 channel regulate neuronal excitability in the pathogenesis of mesial temporal lobe epilepsy"],"prefix":"10.1038","volume":"14","author":[{"given":"Yuting","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiyan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongrong","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaomei","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuo","family":"Kuang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liwen","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,2,28]]},"reference":[{"key":"52399_CR1","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/s00726-010-0638-8","volume":"40","author":"L Wu","year":"2011","unstructured":"Wu, L. et al. 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