Activation of group III metabotropic glutamate receptors attenuates rotenone toxicity on dopaminergic neurons through a microtubule-dependent mechanism.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Qian JiangJian Feng

Abstract

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. ...Continue Reading

Citations

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