RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion
RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion
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DOI：
10.1038/nn1700
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发表时间：
2006-06-01
影响因子：
25
通讯作者：
Surmeier, D. James
中科院分区：
文献类型：
--
作者：
Ding, Jun;Guzman, Jaime N.;Surmeier, D. James
帕金森病是一种神经退行性疾病，其症状是由支配纹状体的多巴胺能神经元丢失引起的。随着纹状体多巴胺水平的下降，纹状体乙酰胆碱的释放增加，加剧了运动症状。这种适应通常被归因于D-2多巴胺受体抑制的神经元间调节的丧失。我们的结果指向了一种完全不同的新机制。纹状体多巴胺耗竭后，D2多巴胺受体对控制中间神经元囊泡性乙酰胆碱释放的钙通道的调节作用不变，但M-4受体与这些通道的偶联作用明显减弱。这种适应归因于RGS4的上调，RGS4是一种自身受体相关的GTPase加速蛋白。这种特定的信号适应延伸到更广泛的自身受体对神经元间尖峰放电的控制的丧失。这些观察表明，依赖RGS4的神经元间自身受体信号的减弱是帕金森病纹状体乙酰胆碱释放增加的主要因素。
Parkinson disease is a neurodegenerative disorder whose symptoms are caused by the loss of dopaminergic neurons innervating the striatum. As striatal dopamine levels fall, striatal acetylcholine release rises, exacerbating motor symptoms. This adaptation is commonly attributed to the loss of interneuronal regulation by inhibitory D-2 dopamine receptors. Our results point to a completely different, new mechanism. After striatal dopamine depletion, D2 dopamine receptor modulation of calcium (Ca2+) channels controlling vesicular acetylcholine release in interneurons was unchanged, but M-4 muscarinic autoreceptor coupling to these same channels was markedly attenuated. This adaptation was attributable to the upregulation of RGS4-an autoreceptor-associated, GTPase-accelerating protein. This specific signaling adaptation extended to a broader loss of autoreceptor control of interneuron spiking. These observations suggest that RGS4-dependent attenuation of interneuronal autoreceptor signaling is a major factor in the elevation of striatal acetylcholine release in Parkinson disease.