Bibliographic Details
| Title: |
PLPP/CIN-mediated NF2 S10 dephosphorylation distinctly regulates kainate-induced seizure susceptibility and neuronal death through PAK1-NF-κB-COX-2-PTGES2 signaling pathway |
| Authors: |
Ji-Eun Kim, Duk-Shin Lee, Tae-Hyun Kim, Hana Park, Min-Ju Kim, Tae-Cheon Kang |
| Source: |
Journal of Neuroinflammation, Vol 20, Iss 1, Pp 1-16 (2023) |
| Publisher Information: |
BMC, 2023. |
| Publication Year: |
2023 |
| Collection: |
LCC:Neurology. Diseases of the nervous system |
| Subject Terms: |
COX-2, IPA-3, Merlin, NF-κB, NF2, PAK1, Neurology. Diseases of the nervous system, RC346-429 |
| More Details: |
Abstract Background Pyridoxal-5′-phosphate phosphatase/chronophin (PLPP/CIN) selectively dephosphorylates serine (S) 10 site on neurofibromin 2 (NF2, also known as merlin (moesin-ezrin-radixin-like protein) or schwannomin). p21-activated kinase 1 (PAK1) is a serine/threonine protein kinase, which is involved in synaptic activity and plasticity in neurons. NF2 and PAK1 reciprocally regulate each other in a positive feedback manner. Thus, the aim of the present study is to investigate the effects of PLPP/CIN-mediated NF2 S10 dephosphorylation on PAK1-related signaling pathways under physiological and neuroinflammatory conditions, which are largely unknown. Methods After kainate (KA) injection in wild-type, PLPP/CIN −/− and PLPP/CIN Tg mice, seizure susceptibility, PAK1 S204 autophosphorylation, nuclear factor-κB (NF-κB) p65 S276 phosphorylation, cyclooxygenase-2 (COX-2) upregulation, prostaglandin E synthase 2 (PTGES2) induction and neuronal damage were measured. The effects of 1,1'-dithiodi-2-naphthtol (IPA-3, a selective inhibitor of PAK1) pretreatment on these responses to KA were also validated. Results PLPP/CIN overexpression increased PAK1 S204 autophosphorylation concomitant with the enhanced NF2 S10 dephosphorylation in hippocampal neurons under physiological condition. Following KA treatment, PLPP/CIN overexpression delayed the seizure on-set and accelerated PAK1 S204 phosphorylation, NF-κB p65 S276 phosphorylation, COX-2 upregulation and PTGES2 induction, which were ameliorated by PLPP/CIN deletion or IPA-3. Furthermore, IPA-3 pretreatment shortened the latency of seizure on-set without affecting seizure severity (intensity) and ameliorated CA3 neuronal death induced by KA. Conclusions These findings indicate that PLPP/CIN may regulate seizure susceptibility (the latency of seizure on-set) and CA3 neuronal death in response to KA through NF2-PAK1-NF-κB-COX-2-PTGES2 signaling pathway. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1742-2094 |
| Relation: |
https://doaj.org/toc/1742-2094 |
| DOI: |
10.1186/s12974-023-02788-9 |
| Access URL: |
https://doaj.org/article/bcfbb42313e74969939c727a7eea4f8a |
| Accession Number: |
edsdoj.bcfbb42313e74969939c727a7eea4f8a |
| Database: |
Directory of Open Access Journals |
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