Effect of dopamine denervation and dopamine agonist administration on serine phosphorylation of striatal nmda receptor subunits
Effect of dopamine denervation and dopamine agonist administration on serine phosphorylation of striatal nmda receptor subunits
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DOI：
10.1016/s0006-8993(99)01121-x
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发表时间：
1999-03-13
期刊：
影响因子：
2.9
通讯作者：
Chase, TN
中科院分区：
文献类型：
--
作者：
Oh, JD;Vaughan, CL;Chase, TN
纹状体N-甲基-D-天冬氨酸（NMDA）受体的致敏作用与帕金森病动物和患者的拟多巴胺治疗相关的反应改变的发病机制有关。为了确定是否NMDA受体亚基的丝氨酸磷酸化激活的Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）有助于这一过程，我们研究了单侧黑质纹状体消融与B-羟基多巴胺和随后的治疗左旋多巴，SKF 38393（D1-偏好多巴胺激动剂），或quinpirole（D2-偏好激动剂）对运动反应和磷酸化状态的影响。每天两次给予大鼠左旋多巴三周，缩短了其对左旋多巴或SKF 38393激发的旋转反应的持续时间，但延长了喹吡罗诱导的旋转的持续时间。同时，左旋多巴处理提高了纹状体NR 2A亚基的丝氨酸磷酸化水平（p < 0.02），但NR 2B亚基的丝氨酸磷酸化水平没有相关的亚基蛋白水平变化。SKF 38393长期治疗增加了NR 2A（p < 0.0001），但减少了NR 2B（p < 0.004）丝氨酸磷酸化。相比之下，长期喹吡罗治疗对NR 2A没有影响，但增加了NR 2B磷酸化（p < 0.0001）。急性纹状体内注射CaMKII抑制剂KN 93（1.0 μ g）不仅使左旋多巴诱导的运动反应改变正常化，而且还分别减弱了D1和D2受体介导的NR 2A和NR 2B亚基的丝氨酸磷酸化（p < 0.02）。这些结果表明，间歇性刺激D1或D2多巴胺能受体引起的NMDA受体亚基丝氨酸磷酸化的CaMK II介导的上升有助于纹状体NMDA受体敏感性的明显增强，从而导致左旋多巴治疗的帕金森病大鼠的多巴胺能反应可塑性。(C)1999 Elsevier Science B. V.保留所有权利。
Sensitization of striatal N-methyl-D-aspartate (NMDA) receptors has been implicated in the pathogenesis of the response alterations associated with dopaminomimetic treatment of parkinsonian animals and patients. To determine whether serine phosphorylation of NMDA receptor subunits by activation of Ca2+/calmodulin-dependent protein-kinase Il (CaMKII) contributes to this process, we examined the effects of unilateral nigrostriatal ablation with B-hydroxydopamine and subsequent treatment with levodopa, SKF 38393 (D1-preferring dopamine agonist), or quinpirole (D2-preferring agonist) on motor responses and phosphorylation states. Three weeks of twice-daily levodopa administration to rats shortened the duration of their rotational response to levodopa or SKF 38393 challenge, but prolonged the duration of quinpirole-induced rotation. At the same time, levodopa treatment elevated serine phosphorylation of striatal NR2A (p < 0.02), but not that of NR2B subunits, without associated changes in subunit protein levels. Chronic treatment with SKF 38393 increased NR2A (p < 0.0001) but decreased NR2B (p < 0.004) serine phosphorylation. In contrast, chronic quinpirole treatment had no effect on NR2A but increased NR2B phosphorylation (p < 0.0001). The acute intrastriatal injection of the CaMKII inhibitor KN93 (1.0 mu g) not only normalized the levodopa-induced motor response alterations but also attenuated the D1 and D2 receptor-mediated serine phosphorylation of NR2A and NR2B subunits, respectively (p < 0.02). These results suggest that a CaMKII-mediated rise in serine phosphorylation of NMDA receptor subunits induced by intermittent stimulation of D1 or D2 dopaminergic receptors contributes to the apparent enhancement in striatal NMDA receptor sensitivity and thus to the dopaminergic response plasticity in levodopa-treated parkinsonian rats. (C) 1999 Elsevier Science B.V. All rights reserved.