Girault J A, Siciliano J C, Robel L, Hervé D
Institut National de la Santé et de la Recherche Médicale U 114, Chaire de Neuropharmacologie, Collège de France, Paris.
Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2769-73. doi: 10.1073/pnas.89.7.2769.
Even though the short-term actions of dopamine on postsynaptic receptors are well-characterized, the molecular bases for long-term trophic interactions between dopamine neurons and their targets remain unclear. Since protein-tyrosine phosphorylation plays a key role in the action of trophic factors, we have investigated its possible involvement in the interactions between dopamine neurons and their striatal targets. Lesioning rat nigrostriatal dopamine neurons by using 6-hydroxydopamine increased the phosphorylation on tyrosine of several proteins, including a major 180-kDa protein (pp180) in the ipsilateral striatum. Protein-tyrosine kinase activity was also increased in the striatum ipsilateral to the lesion, whereas no change in phosphotyrosine phosphatase activity was detected. The stimulation of pp180 phosphorylation was observed 1, 2, and 8 weeks after 6-hydroxydopamine lesion, was selective for the destruction of dopamine neurons, and was mimicked by chronic blockade of dopamine receptors with neuroleptics. Additional lesion experiments and subcellular fractionation showed that pp180 is located in neuronal postsynaptic densities, suggesting that pp180 is a postsynaptic component of corticostriatal synapses. Our results indicate that lesion of specific afferent fibers can activate tyrosine phosphorylation in central neurons and suggest that tyrosine phosphorylation is involved in the long-term consequences of dopamine deficiency and may play a role in synaptic plasticity.
尽管多巴胺对突触后受体的短期作用已得到充分表征，但多巴胺神经元与其靶标之间长期营养相互作用的分子基础仍不清楚。由于蛋白质酪氨酸磷酸化在营养因子的作用中起关键作用，我们研究了其可能参与多巴胺神经元与其纹状体靶标之间的相互作用。通过使用6-羟基多巴胺损伤大鼠黑质纹状体多巴胺神经元，增加了几种蛋白质酪氨酸的磷酸化，包括同侧纹状体中的一种主要的180 kDa蛋白质（pp180）。损伤同侧纹状体中的蛋白质酪氨酸激酶活性也增加，而未检测到磷酸酪氨酸磷酸酶活性的变化。在6-羟基多巴胺损伤后1、2和8周观察到pp180磷酸化的刺激，对多巴胺神经元的破坏具有选择性，并且可以通过用抗精神病药物慢性阻断多巴胺受体来模拟。额外的损伤实验和亚细胞分级分离表明，pp180位于神经元突触后致密物中，表明pp180是皮质纹状体突触的突触后成分。我们的结果表明，特定传入纤维的损伤可以激活中枢神经元中的酪氨酸磷酸化，并表明酪氨酸磷酸化参与多巴胺缺乏的长期后果，可能在突触可塑性中起作用。
