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Effects of nicotinic acetylcholine receptor overexpression in neuronal cells.

烟碱乙酰胆碱受体过度表达对神经元细胞的影响。

基本信息

批准号：
14570614
负责人：
UTSUGISAWA Kimiaki
金额：
$ 1.98万
依托单位：
Iwate Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570614/
关键词：
α7nAChR Angiotensin II Cell cycle Extracellular-signal-regulated kinase Hypoxia Neurite outgrowth PC12 Protein kinase Cδ AT1 AT2 candesartan proten kinase C δ Cell death ニコチン性アセチルコリン受容体 α7サブタイプ extracellular-signal-regulated

项目摘要

PC12 cells transfected with the α7nAChR cDNA, independent of agonistic stimulation, exhibited to start the sustained expression of phospho-extracellular-signal-regulated kinases (ERKs) as immediately as expression of α 7 subunit protein after transfection. PC12 cells over-expressing α7nAChR showed high migration ability, marked neurite outgrowth, adherence to the culture dish and an increase in expression of surface N-cadherin, whereas their proliferation activity was low. Examination of cell cycle distribution showed an increase in the proportion of G2-phase cells in PC12 cells over-expressing α 7nAChR. These findings suggest that, over-expression of α7nAChR induces sustained activation of ERK, which probably promotes the functions of neuron-specific Cdks and differentiation-like transformation. The cytoskeletal machinery necessary for sufficient expression of α7nAChR may have some links to ERK and Cdk signals promoting neurite outgrowth, and their declines in the elderly may deterior … More ate neuronal plasticity.To investigate the role of protein kinase Cδ (PKCδ) in angiotensin II -induced facilitation mechanisms of hypoxic neuronal damage and whether candesartan, an AT1 receptor antagonist, can suppress these mechanisms, we performed in vitro experiments using PC12 cells under hypoxic/reoxygenation conditions. Angiotensin II increased the basal expression level of PKCδ phosphorylated at Ser643 before hypoxia, promoted the cleavage of PKC δ to its catalytic fragment, and fostered the progression of DNA fragmentation after hypoxia. Candesartan inhibited both phosphorylation and cleavage of PKCδ and suppressed the angiotensin II -induced facilitation of DNA fragmentation. In PC12 cells expressing the ATP-binding mutant of PKCδ acting as a dominant-negative protein, DNA fragmentation was markedly suppressed regardless of the presence of angiotensin II. These findings suggest that angiotensin II -induced facilitation of DNA fragmentation under hypoxic conditions is mediated by PKCδ, and the mechanisms can be suppressed by the candesartan mediated blockade of the AT1 receptor. Less

用α 7 nAChR cDNA转染的PC 12细胞，不依赖于激动剂刺激，表现出在转染后立即开始持续表达磷酸化细胞外信号调节激酶（ERK）和表达α 7亚基蛋白。过表达α 7 nAChR的PC 12细胞具有较强的迁移能力，突起生长明显，贴壁能力强，细胞表面N-cadherin表达增加，而增殖活性较低。细胞周期分析显示，α 7 nAChR过表达的PC 12细胞中G2期细胞比例增加。这些结果表明，α 7 nAChR的过表达可诱导ERK的持续激活，从而促进神经元特异性Cdks的功能和分化样转化。α 7 nAChR充分表达所必需的细胞骨架机制可能与ERK和Cdk信号促进轴突生长有关，老年人中它们的下降可能与神经元的生长有关。 ...更多信息为了研究蛋白激酶Cδ（PKCδ）在血管紧张素II诱导的缺氧性神经元损伤易化机制中的作用以及AT 1受体拮抗剂坎地沙坦是否能抑制这些机制，我们在体外用PC 12细胞进行了缺氧/复氧条件下的实验。血管紧张素II可增加缺氧前PKCδ Ser 643磷酸化的基础表达水平，促进PKC δ裂解为催化片段，促进缺氧后DNA断裂的进程。坎地沙坦抑制PKCδ的磷酸化和切割，并抑制血管紧张素II诱导的DNA片段化。在表达PKCδ的ATP结合突变体（作为显性负性蛋白）的PC 12细胞中，无论是否存在血管紧张素II，DNA片段化均受到显著抑制。这些结果表明，在缺氧条件下，血管紧张素II诱导的DNA片段化的易化是由PKCδ介导的，并且该机制可以被坎地沙坦介导的AT 1受体阻断剂抑制。少