{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:13:38Z","timestamp":1787498018982,"version":"build-2736575974"},"reference-count":72,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T00:00:00Z","timestamp":1608163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002632","name":"Hallym University","doi-asserted-by":"publisher","award":["HRF-202010-005"],"award-info":[{"award-number":["HRF-202010-005"]}],"id":[{"id":"10.13039\/501100002632","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Both \u03b1-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) have been reported as targets for treatment of epilepsy. To investigate the roles and interactions of AMPAR and NMDAR in ictogenesis of epileptic hippocampus, we analyzed AMPAR antagonists (perampanel and GYKI 52466)-mediated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulation and glutamate ionotropic receptor NMDA type subunit 2B (GluN2B) tyrosine (Y) 1472 phosphorylation in epilepsy rats. Both perampanel and GYKI 52466 increased PTEN expression and its activity (reduced phosphorylation), concomitant with decreased activities (phosphorylations) of Src family-casein kinase 2 (CK2) signaling pathway. Compatible with these, they also restored the upregulated GluN2B Y1472 and Ca2+\/cAMP response element-binding protein (CREB) serine (S) 133 phosphorylations and surface expression of glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) to basal level in the epileptic hippocampus. These effects of perampanel and GYKI 52466 are observed in responders (whose seizure activities are responsive to AMPAR antagonists), but not non-responders (whose seizure activities were uncontrolled by AMPAR antagonists). Therefore, our findings suggest that Src\/CK2\/PTEN-mediated GluN2B Y1472 and CREB S133 regulations may be one of the responsible signaling pathways for the generation of refractory seizures in non-responders to AMPAR antagonists.<\/jats:p>","DOI":"10.3390\/ijms21249633","type":"journal-article","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T10:42:47Z","timestamp":1608201767000},"page":"9633","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Src\/CK2\/PTEN-Mediated GluN2B and CREB Dephosphorylations Regulate the Responsiveness to AMPA Receptor Antagonists in Chronic Epilepsy Rats"],"prefix":"10.3390","volume":"21","author":[{"given":"Ji-Eun","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, Korea"},{"name":"Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duk-Shin","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, Korea"},{"name":"Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hana","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, Korea"},{"name":"Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae-Cheon","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon 24252, Korea"},{"name":"Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon 24252, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1212\/WNL.0000000000003509","article-title":"Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies","volume":"88","author":"Fiest","year":"2017","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1093\/brain\/awh726","article-title":"Natural history of treated childhood-onset epilepsy: Prospective, long-term population-based study","volume":"129","author":"Schmidt","year":"2006","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1602\/neurorx.2.1.86","article-title":"Blood-brain barrier active efflux transporters: ATP-binding cassette gene family","volume":"2","author":"Potschka","year":"2005","journal-title":"NeuroRx"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/s41582-019-0217-x","article-title":"Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy","volume":"15","author":"Vezzani","year":"2019","journal-title":"Nat. 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