Activation of group III metabotropic glutamate receptors attenuates rotenone toxicity on dopaminergic neurons through a microtubule-dependent mechanism
Activation of group III metabotropic glutamate receptors attenuates rotenone toxicity on dopaminergic neurons through a microtubule-dependent mechanism
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DOI：
10.1523/jneurosci.0118-06.2006
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发表时间：
2006-04-19
影响因子：
5.3
通讯作者：
Feng, J
中科院分区：
文献类型：
--
作者：
Jiang, Q;Yan, Z;Feng, J
鱼藤酮是一种广泛使用的农药，在动物模型中，全身给药会导致黑质多巴胺能（DA）神经元的选择性变性和帕金森病样症状。我们之前的研究表明鱼藤酮的微管解聚活性在其对大鼠胚胎中脑神经元培养中酪氨酸羟化酶阳性（TH+）神经元的选择性毒性中起关键作用。本研究表明，III组代谢性谷氨酸受体（mGluRIII）激动剂（如L-AP-4）的应用显著降低了鱼藤酮对培养中脑TH+神经元的毒性。L-AP-4的保护作用被微管相关蛋白激酶（MAP）激酶（MEK）的药理抑制或MEK1的过表达所抵消，提示其依赖于MAP激酶级联反应。我们发现L-AP-4通过动力蛋白、β -阻滞蛋白2和Src介导的途径诱导MAP激酶细胞外信号调节激酶（ERK）的快速和短暂激活。ERK以这种方式激活的目标是细胞质而不是核底物。与此一致的是，L-AP-4以mek依赖的方式显著减弱鱼藤酮或秋水草碱诱导的微管解聚。此外，L-AP-4还以mek依赖性的方式降低了秋水仙碱对TH+神经元的毒性。L-AP-4对鱼藤酮毒性的保护作用被微管稳定剂紫杉醇所阻断。综上所述，这些结果表明III组代谢性谷氨酸受体的激活通过激活MAP激酶途径来稳定微管，从而减弱鱼藤酮对DA神经元的选择性毒性。这些发现可能为鱼藤酮诱导的帕金森症提供一种新的神经保护方法。
Systemic administration of rotenone, a widely used pesticide, causes selective degeneration of nigral dopaminergic (DA) neurons and Parkinson's disease-like symptoms in animal models. Our previous study has shown that the microtubule-depolymerizing activity of rotenone plays a critical role in its selective toxicity on tyrosine hydroxylase-positive (TH+) neurons in rat embryonic midbrain neuronal cultures. Here, we show that application of group III metabotropic glutamate receptor (mGluRIII) agonists (e.g.,L-AP-4) significantly reduced rotenone toxicity on midbrain TH+ neurons in culture. The protective effect of L-AP-4 was abolished by pharmacological inhibition of the microtubule-associated protein ( MAP) kinase kinase (MEK) or overexpression of dominant-negative MEK1, suggesting its dependence on the MAP kinase cascade. We found that L-AP-4 induced a rapid and transient activation of the MAP kinase extracellular signal-regulated kinase (ERK) through a pathway mediated by dynamin, beta-arrestin 2, and Src. ERK activated in this manner targeted cytosolic rather than nuclear substrates. Consistent with this, L-AP-4 significantly attenuated rotenone-or colchicine-induced microtubule depolymerization in an MEK-dependent manner. Moreover, L-AP-4 decreased colchicine toxicity on TH+ neurons in an MEK-dependent manner as well. The protective effect of L-AP-4 against rotenone toxicity was occluded by the microtubule-stabilizing agent Taxol. Together, these results suggest that activation of group III metabotropic glutamate receptors attenuates the selective toxicity of rotenone on DA neurons by activating the MAP kinase pathway to stabilize microtubules. These findings may offer a novel neuroprotective approach against rotenone-induced parkinsonism.