Protein kinase Mζ is involved in the modulatory effect of fluoxetine on hippocampal neurogenesis in vitro.
Protein kinase Mζ is involved in the modulatory effect of fluoxetine on hippocampal neurogenesis in vitro.
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DOI：
10.1017/s1461145714000364
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发表时间：
2014-09
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影响因子：
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通讯作者：
Ying Xin Wang;Xiang-rong Zhang;Z. J. Zhang;Lei Li;G. Xi;Di Wu;Yan Wang
中科院分区：
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作者：
Ying Xin Wang;Xiang-rong Zhang;Z. J. Zhang;Lei Li;G. Xi;Di Wu;Yan Wang
慢性选择性5 -羟色胺再摄取抑制剂（SSRIs）对抑郁症的疗效与持续应激和糖皮质激素升高相关的海马神经发生缺陷的恢复是平行的。以往的研究表明，非典型蛋白激酶C （aPKC）参与神经发生和抗抑郁反应的调节。特异性aPKC亚型（PKCζ， PKMζ和PKCι）是否参与ssri诱导的海马神经发生及其潜在机制尚不清楚。目前的研究表明，PKMζ和PKCι而不是PKCζ在大鼠胚胎海马神经干细胞（NSCs）中表达，而PKMζ而不是PKCι的表达在糖皮质激素受体激动剂地塞米松不存在和不存在的情况下都被SSRI氟西汀增加。PKMζ shRNA显著抑制神经元的增殖和神经元定向分化，增加NSC的凋亡，阻断氟西汀对NSC神经发生的刺激作用。氟西汀在没有和存在地塞米松的情况下，以5-羟色胺- 1a （5-HT1A）受体依赖的方式显著增加海马NSCs中PKMζ的表达。PKMζ肽阻断剂ZIP和MEK抑制剂U0126在氟西汀和5-HT1A受体激动剂8-OH DPAT的作用下，显著抑制丝裂原活化蛋白激酶（MAPK）通路中细胞外信号调节激酶1/2和环腺苷单磷酸反应元件结合蛋白磷酸化和海马NSC神经发生的增加。总的来说，我们的研究结果表明，SSRI氟西汀通过pkm - ζ介导的机制增加了海马NSC神经发生，该机制将5-HT1A受体激活与下游MAPK信号通路的磷酸化联系起来。
The efficacy of chronic selective serotonin reuptake inhibitors (SSRIs) on depression is paralleled by the recovery of deficits in hippocampal neurogenesis related to sustained stress and elevated glucocorticoids. Previous studies have shown that atypical protein kinase C (aPKC) is implicated in the regulation of neurogenesis and the antidepressant response. Whether the specific aPKC isoforms (PKCζ, PKMζ and PKCι) are involved in SSRI-induced hippocampal neurogenesis and the underlying mechanisms is unknown. The present study shows that PKMζ and PKCι but not PKCζ are expressed in rat embryonic hippocampal neural stem cells (NSCs), whereas PKMζ but not PKCι expression is increased by the SSRI fluoxetine both in the absence and presence of the glucocorticoid receptor agonist dexamethasone. PKMζ shRNA significantly decreased neuronal proliferation and neuron-oriented differentiation, increased NSC apoptosis, and blocked the stimulatory effect of fluoxetine on NSC neurogenesis. Fluoxetine significantly increased PKMζ expression in hippocampal NSCs in a 5-hydroxytryptamine-1A (5-HT1A) receptor-dependent manner in both the absence and presence of dexamethasone. The PKMζ peptide blocker ZIP and MEK inhibitor U0126 significantly inhibited the increase in extracellular signal-regulated kinase 1/2 and cyclic adenosine monophosphate response element binding protein phosphorylation in the mitogen-activated protein kinase (MAPK) pathway and hippocampal NSC neurogenesis in response to fluoxetine and the 5-HT1A receptor agonist 8-OH DPAT. Collectively, our results suggest that the SSRI fluoxetine increases hippocampal NSC neurogenesis via a PKMζ-mediated mechanism that links 5-HT1A receptor activation with the phosphorylation of the downstream MAPK signaling pathway.