Chronic lithium-induced down-regulation of MARCKS in immortalized hippocampal cells: potentiation by muscarinic receptor activation.
Chronic lithium-induced down-regulation of MARCKS in immortalized hippocampal cells: potentiation by muscarinic receptor activation.
复制标题
锂诱导的永生化海马细胞中 MARCKS 的慢性下调：毒蕈碱受体激活的增强作用。
DOI：
10.1046/j.1471-4159.1996.67020767.x
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发表时间：
1996
影响因子：
4.7
通讯作者：
Lenox,RH
中科院分区：
文献类型：
--
作者：
Watson,DG;Lenox,RH
我们实验室先前的研究表明，大鼠长期接触锂会导致海马蛋白激酶 C (PKC) 磷蛋白底物 MARCKS（富含肉豆蔻酰化丙氨酸的 C 激酶底物）水平显着降低，这种情况在停药后持续存在，但在急性给药后不会观察到。在永生化海马细胞系 (HN33) 中，我们确定佛波酯快速下调 PKC 活性，并导致随后的 PKC 依赖性 MARCKS 蛋白含量减少。我们现在报道，HN33 细胞长期暴露于 LiCl (1-10 mM) 会产生剂量和时间依赖性的 MARCKS 蛋白下调。锂诱导的 MARCKS 减少取决于培养基中肌醇的浓度，并且在肌醇浓度升高的情况下会逆转并被阻止。当 HN33 细胞在限制肌醇条件下暴露于临床相关浓度 (1 mM) 的锂时，毒蕈碱受体偶联的磷酸肌醇信号传导的激活显着增强了锂诱导的 MARCKS 蛋白的下调。有人认为，锂在大脑中的主要作用与其通过肌醇三磷酸/二酰甘油途径在受体介导的信号传导中的肌醇单磷酸酶抑制活性有关，从而导致相对的肌醇消耗。我们的数据提供的证据表明，锂的这种初始作用可能转化为海马中 MARCKS 蛋白表达的 PKC 依赖性长期下调。
Previous studies in our laboratory have demonstrated that exposure of rats to chronic lithium results in a significant reduction in the hippocampus of levels of the protein kinase C (PKC) phosphoprotein substrate MARCKS (myristoylated alanine‐rich C kinase substrate), which persists after withdrawal and is not observed following acute administration. In an immortalized hippocampal cell line (HN33), we have determined that phorbol esters rapidly down‐regulate PKC activity and lead to a subsequent PKC‐dependent reduction in content of MARCKS protein. We now report that chronic exposure of HN33 cells to LiCl (1–10 mM) produces a dose‐ and time‐dependent down‐regulation of MARCKS protein. The lithium‐induced reduction in MARCKS is dependent on the concentration of inositol present in the medium and is reversed and prevented in the presence of elevated inositol concentrations. When HN33 cells were exposed to lithium at clinically relevant concentrations (1 mM) under limiting inositol conditions, activation of muscarinic receptor‐coupled phosphoinositide signaling significantly potentiated the lithium‐induced down‐regulation of MARCKS protein. It has been suggested that a major action of lithium in the brain is linked to its inositol monophosphatase inhibitory activity in receptor‐mediated signaling through the inositol trisphosphate/diacylglycerol pathway, resulting in a relative inositol depletion. Our data provide evidence that this initial action of lithium may translate into a PKC‐dependent long‐term down‐regulation of MARCKS protein expression in the hippocampus.