Roles of Ca(2+)/calmodulin-dependent protein kinase II in subcellular expression of striatal N-methyl-D-aspartate receptors in l-3, 4-dihydroxyphenylalanine-induced dyskinetic rats.
Roles of Ca(2+)/calmodulin-dependent protein kinase II in subcellular expression of striatal N-methyl-D-aspartate receptors in l-3, 4-dihydroxyphenylalanine-induced dyskinetic rats.
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Ca2 /钙调蛋白依赖性蛋白激酶 II 在 L-3,4-二羟基苯丙氨酸诱导的运动障碍大鼠纹状体 N-甲基-D-天冬氨酸受体亚细胞表达中的作用
DOI：
10.2147/dddt.s73868
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Liu Z
中科院分区：
文献类型：
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作者：
Gan J;Qi C;Liu Z
n -甲基-d -天冬氨酸（NMDA）受体在帕金森病（PD）中l-3,4-二羟基苯丙氨酸（l-DOPA）诱导的运动障碍（LID）的发展中起着至关重要的作用。Ca2+/钙调素依赖性蛋白激酶II （CaMKII）被认为调节LID中NMDA受体的表达和激活，但LID与CaMKII调节的NMDA受体活性之间的相互作用迄今尚不清楚。我们用6-羟多巴胺损伤大鼠建立PD大鼠模型，在所有PD大鼠和假大鼠损伤纹状体中分别注射或不注射CaMKII抑制剂KN-93后给予至少21天的左旋多巴。表面受体交联试验用于区分纹状体NMDA受体在表面和细胞内的表达。l-DOPA处理提高了GluN1的表面表达水平，降低了其细胞内表达水平，但没有改变受损纹状体中GluN1蛋白的总水平。相比之下，l-DOPA降低GluN2A表面表达，但增加其细胞内表达。l-DOPA优先增加GluN2B在表面间室的表达。我们还发现左旋多巴增加了纹状体神经元T286的CaMKII自磷酸化。通过向受损纹状体微注射CaMKII抑制剂jk -93对CaMKII的抑制很大程度上逆转了左旋多巴诱导的三个亚单位的变化。此外，KN-93治疗后，动物的运动障碍行为得到了缓解。我们的研究表明，长期左旋多巴可以激活纹状体神经元的CaMKII。活化的CaMKII至少部分参与介导l- dopa诱导的NMDA受体表面/细胞内表达的变化。
The role of N-Methyl-D-aspartate (NMDA) receptors is critical to the development of l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID) in Parkinson’s disease (PD). Ca2+/calmodulin-dependent protein kinase II (CaMKII) is thought to regulate the expression and activation of NMDA receptors in LID, but the interaction between LID and CaMKII-modulated NMDA receptor activity is not clear so far. We used 6-hydroxydopamine-lesioned rats to create PD rat model, and at least 21 days of l-DOPA was administrated followed with or without microinjection of CaMKII inhibitor KN-93 into the lesioned striatum of all the PD rats and sham rats. A surface receptor cross-linking assay was used to distinguish expression of striatal NMDA receptors in surface and intracellular compartments. l-DOPA treatment enhanced surface levels of GluN1 expression and reduced its intracellular expression, but did not change total levels of GluN1 protein in the lesioned striatum. In contrast, l-DOPA decreased GluN2A surface expression but increased its intracellular expression. l-DOPA increased GluN2B expression preferentially in the surface compartment. We also found that l-DOPA increased CaMKII autophosphorylation at T286 in striatal neurons. The inhibition of CaMKII by microinjecting CaMKII inhibitor KN-93 into the lesioned striatum largely reversed the l-DOPA-induced changes in three subunits. In addition, dyskinetic behaviors of animals were observed alleviated after treatment of KN-93. Our research indicates that long-term l-DOPA administration activates CaMKII in striatal neurons. Activated CaMKII is involved at least in part in mediating l-DOPA-induced changes of NMDA receptors surface/intracellular expression.