PDF(Pubmed)
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/CINTg 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.
METHODS: After kainate (KA) injection in wild-type, PLPP/CIN-/- and PLPP/CINTg 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.
摘要：
背景：吡哆醛-5'-磷酸磷酸酶/时钟蛋白（PLPP/CIN）选择性去磷酸化神经纤维蛋白2（NF2，也称为merlin（moesin-ezrin-radixin-like蛋白）或schwannomin）上的丝氨酸（S）10位点。p21激活激酶1（PAK1）是一种丝氨酸/苏氨酸蛋白激酶，参与神经元的突触活动和可塑性。NF2和PAK1以正反馈方式相互调节。因此，本研究的目的是研究PLPP/CIN介导的NF2S10去磷酸化对生理和神经炎症条件下PAK1相关信号通路的影响,这在很大程度上是未知的。
方法：野生型红藻氨酸（KA）注射后，PLPP/CIN-/-和PLPP/CINTg小鼠，癫痫发作易感性，PAK1S204自磷酸化，核因子-κB(NF-κB)p65S276磷酸化,环氧合酶-2（COX-2）上调，测量前列腺素E合酶2（PTGES2）的诱导和神经元损伤。还验证了1,1'-二硫代-2-萘酚（IPA-3，PAK1的选择性抑制剂）预处理对这些对KA的反应的影响。
结果：在生理条件下，PLPP/CIN过表达增加了PAK1S204自磷酸化，同时增强了NF2S10去磷酸化。KA治疗后,PLPP/CIN过表达延迟癫痫发作并加速PAK1S204磷酸化，NF-κBp65S276磷酸化,COX-2上调和PTGES2诱导，通过PLPP/CIN缺失或IPA-3改善。此外，IPA-3预处理在不影响癫痫发作严重程度（强度）的情况下缩短了癫痫发作的潜伏期，并改善了KA诱导的CA3神经元死亡。
结论：这些研究结果表明，PLPP/CIN可能通过NF2-PAK1-NF-κB-COX-2-PTGES2信号通路调节对KA的癫痫易感性（癫痫发作潜伏期）和CA3神经元死亡。
方法：野生型红藻氨酸（KA）注射后，PLPP/CIN-/-和PLPP/CINTg小鼠，癫痫发作易感性，PAK1S204自磷酸化，核因子-κB(NF-κB)p65S276磷酸化,环氧合酶-2（COX-2）上调，测量前列腺素E合酶2（PTGES2）的诱导和神经元损伤。还验证了1,1'-二硫代-2-萘酚（IPA-3，PAK1的选择性抑制剂）预处理对这些对KA的反应的影响。
结果：在生理条件下，PLPP/CIN过表达增加了PAK1S204自磷酸化，同时增强了NF2S10去磷酸化。KA治疗后,PLPP/CIN过表达延迟癫痫发作并加速PAK1S204磷酸化，NF-κBp65S276磷酸化,COX-2上调和PTGES2诱导，通过PLPP/CIN缺失或IPA-3改善。此外，IPA-3预处理在不影响癫痫发作严重程度（强度）的情况下缩短了癫痫发作的潜伏期，并改善了KA诱导的CA3神经元死亡。
结论：这些研究结果表明，PLPP/CIN可能通过NF2-PAK1-NF-κB-COX-2-PTGES2信号通路调节对KA的癫痫易感性（癫痫发作潜伏期）和CA3神经元死亡。
