D1 dopamine receptor supersensitivity in the dopamine-depleted striatum results from a switch in the regulation of ERK1/2/MAP kinase
D1 dopamine receptor supersensitivity in the dopamine-depleted striatum results from a switch in the regulation of ERK1/2/MAP kinase
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DOI：
10.1523/jneurosci.22-12-05042.2002
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发表时间：
2002-06-15
影响因子：
5.3
通讯作者：
Brown, P
中科院分区：
文献类型：
--
作者：
Gerfen, CR;Miyachi, S;Brown, P
纹状体中的多巴胺效应主要通过D1和D2多巴胺受体亚型介导，其被分离到直接和间接纹状体投射神经元。黑质纹状体多巴胺系统变性后，直接通路神经元对D1多巴胺受体激动剂表现出超敏反应，这通过诱导立即早期基因（IEGs）如c-fos来证明。在这里，我们表明，使用受体介导的信号转导，包括蛋白磷酸化和诱导的IEGs的分析，D1多巴胺受体超敏性是由于开关ERK 1/2/MAP激酶（细胞外信号调节激酶/丝裂原活化蛋白激酶）在直接通路神经元。正常情况下，在多巴胺完整的纹状体，ERK 1/2/MAP激酶的激活被证明是有限的间接和不直接的通路神经元在皮质纹状体传入刺激。此外，在多巴胺完整的纹状体，治疗与全D1多巴胺受体激动剂或刺激黑质纹状体多巴胺能传入，这两个结果在直接纹状体投射神经元的诱导IEGs，不激活ERK 1/2/MAP激酶。然而，在黑质纹状体多巴胺能通路变性后，ERK 1/2/MAP激酶在直接通路神经元中响应于单独的D1多巴胺受体激动剂或当与皮质纹状体传入刺激组合时被激活。MEK（MAP激酶激酶）的抑制剂负责ERK 1/2/MAP激酶的磷酸化，阻断D1多巴胺受体激动剂在多巴胺耗尽的纹状体中对ERK 1/2/MAP激酶的活化，以及对IEG的超敏感诱导。这些结果表明，多巴胺输入纹状体保持不同形式的蛋白激酶介导的基因调控的直接和间接纹状体投射神经元。
Dopamine effects in the striatum are mediated principally through the D1 and D2 dopamine receptor subtypes, which are segregated to the direct and indirect striatal projection neurons. After degeneration of the nigrostriatal dopamine system, direct pathway neurons display a supersensitive response to D1 dopamine receptor agonists, which is demonstrated by the induction of immediate early genes (IEGs), such as c-fos. Here we show, using analysis of receptor-mediated signal transduction, including protein phosphorylation and induction of IEGs, that D1 dopamine receptor supersensitivity is attributable to a switch to ERK1/2/MAP kinase (extracellular signal-regulated kinase/mitogen-activated protein kinase) in direct pathway neurons. Normally, in the dopamine-intact striatum, activation of ERK1/2/MAP kinase is shown to be restricted to indirect and not direct pathway neurons in response to stimulation of corticostriatal afferents. Moreover, in the dopamine-intact striatum, treatment with full D1 dopamine receptor agonists or stimulation of nigrostriatal dopaminergic afferents, both of which result in the induction of IEGs in direct striatal projection neurons, does not activate ERK1/2/MAP kinase. However, after degeneration of the nigrostriatal dopaminergic pathway, ERK1/2/MAP kinase is activated in direct pathway neurons in response to D1 dopamine receptor agonists either alone or when combined with stimulation of corticostriatal afferents. Inhibitors of MEK (MAP kinase kinase), which is responsible for phosphorylation of ERK1/2/MAP kinase, blocks D1 dopamine receptor agonist activation of ERK1/2/MAP kinase in the dopamine-depleted striatum, as well as the supersensitive induction of IEGs. These results demonstrate that dopamine input to the striatum maintains distinct forms of protein kinase-mediated gene regulation in the direct and indirect striatal projection neurons.