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However, the relationship between CaMKII and neuronal excitability remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Neuronal excitability was detected in\u00a0vivo and in\u00a0vitro by electroencephalography (EEG), patch clamp and multi\u2010electrode array (MEA), respectively. Next, we assessed\u00a0the currents of voltage\u2010gated sodium channels (VGSCs) by patch clamp, and\u00a0 mRNA and protein expressions of VGSCs were determined by\u00a0real\u2010time quantitative reverse transcription\u2010polymerase chain reaction (qRT\u2010PCR) and western blot, respectively. Meanwhile, the association between the nuclear receptor subfamily 4 group A member 2 (\n                      <jats:italic>NR4A2<\/jats:italic>\n                      ) and promoters of\n                      <jats:italic>Scn2a<\/jats:italic>\n                      , was determined by chromatin immunoprecipitation (ChIP)\u2010qPCR. In addition, we utilized co\u2010immunoprecipitation (Co\u2010IP), immunofluorescence labeling, and pull\u2010down to determine the interaction between VGSCs and CaM.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Prolonged CaMKII inhibition by KN93, an inhibitor of CaMKII, for 24\u2009h and CaMKII knockdown induced more seizure\u2010like events in Wistar rats, TRM rats and C57BL\/6 mice, and led to hyperexcitability in primary hippocampal neurons and human induced\u2010pluripotent stem cell (hiPSC)\u2013derived cortical neurons. In addition, prolonged CaMKII inhibition resulted in elevated persistent sodium current (I\n                      <jats:sub>NaP<\/jats:sub>\n                      )\/transient sodium current (I\n                      <jats:sub>NaT<\/jats:sub>\n                      ) and increased mRNA and protein expressions of Na\n                      <jats:sub>V<\/jats:sub>\n                      1.2. Meanwhile, prolonged CaMKII inhibition by KN93 decreased\n                      <jats:italic>NR4A2<\/jats:italic>\n                      expression and contributed to a transcriptional repression role of\n                      <jats:italic>NR4A2<\/jats:italic>\n                      in\n                      <jats:italic>Scn2a<\/jats:italic>\n                      regulation, leading to increased Na\n                      <jats:sub>V<\/jats:sub>\n                      1.2 expression. Moreover, an increased interaction between Na\n                      <jats:sub>V<\/jats:sub>\n                      1.2 and CaM was attributable to enhanced binding of CaM to the isoleucine\u2010glutamine (IQ) domain at the C\u2010terminus of the Na\n                      <jats:sub>V<\/jats:sub>\n                      1.2 channel, which may also lead to the potentiation in I\n                      <jats:sub>NaP<\/jats:sub>\n                      \/I\n                      <jats:sub>NaT<\/jats:sub>\n                      and channel activity. Furthermore, a peptide that antagonized CaM binding to Na\n                      <jats:sub>V<\/jats:sub>\n                      1.2 IQ domain (ACNp) rescued hyperexcitability following prolonged CaMKII inhibition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>\n                      We unveiled that prolonged CaMKII inhibition induced hyperexcitability through increasing the expression of Na\n                      <jats:sub>V<\/jats:sub>\n                      1.2 and its association with CaM. Thus, our study uncovers a novel signaling mechanism by which CaMKII maintains appropriate neuronal excitability.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.18377","type":"journal-article","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T13:23:37Z","timestamp":1742736217000},"page":"2521-2537","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Increased Na\n                    <sub>V<\/sub>\n                    1.2 expression and its interaction with CaM contribute to the hyperexcitability induced by prolonged inhibition of CaMKII"],"prefix":"10.1111","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9935-7779","authenticated-orcid":false,"given":"Hongyue","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology, School of Pharmacy China Medical University  Shenyang 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Ray","family":"Seehus","sequence":"additional","affiliation":[{"name":"Department of Neurobiology Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Developmental Cell Biology China Medical University  Shenyang China"},{"name":"Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, School of Life Sciences China Medical University  Shenyang City Liaoning Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9833-9691","authenticated-orcid":false,"given":"Feng","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Toxicology, School of Pharmacy China Medical University  Shenyang China"},{"name":"Department of Pharmacy The Fourth Affiliated 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