Dopamine D1 receptors mediate CREB phosphorylation via phosphorylation of the NMDA receptor at Ser897-NR1
Dopamine D1 receptors mediate CREB phosphorylation via phosphorylation of the NMDA receptor at Ser897-NR1
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DOI：
10.1046/j.1471-4159.2003.02067.x
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发表时间：
2003-11-01
影响因子：
4.7
通讯作者：
Konradi, C
中科院分区：
文献类型：
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作者：
Dudman, JT;Eaton, ME;Konradi, C
安非他明和可卡因等成瘾药物刺激多巴胺能系统，激活多巴胺受体并诱导整个纹状体的基因表达。从突触处的多巴胺受体刺激到细胞核中的基因表达的信号转导途径尚未完全阐明。在这里，我们提出的证据表明，D1受体刺激导致磷酸化的转录因子Ca2+和环AMP反应元件结合蛋白（CREB）在核内的NMDA受体介导的Ca2+信号。D1受体的刺激通过蛋白激酶A（PKA）诱导NR1亚基上Ser897的磷酸化。该磷酸化事件对于D1受体介导的CREB磷酸化至关重要。多巴胺不能诱导磷酸化缺陷型NR1构建体转染的神经元中CRE介导的基因表达。此外，D1受体的刺激或环AMP水平的增加导致细胞溶质中的Ca2+在谷氨酸的存在下增加，但不是在谷氨酸的情况下，表明多巴胺和环AMP的能力，以促进NMDA通道的活性。D1受体对NMDA受体信号转导通路的募集可能提供了一种基因调控的一般机制，这种机制是药物成瘾和长期记忆机制的基础。
Addictive drugs such as amphetamine and cocaine stimulate the dopaminergic system, activate dopamine receptors and induce gene expression throughout the striatum. The signal transduction pathway leading from dopamine receptor stimulation at the synapse to gene expression in the nucleus has not been fully elucidated. Here, we present evidence that D1 receptor stimulation leads to phosphorylation of the transcription factor Ca2+ and cyclic AMP response element binding protein (CREB) in the nucleus by means of NMDA receptor-mediated Ca2+ signaling. Stimulation of D1 receptors induces the phosphorylation of Ser897 on the NR1 subunit by protein kinase A (PKA). This phosphorylation event is crucial for D1 receptor-mediated CREB phosphorylation. Dopamine cannot induce CRE-mediated gene expression in neurons transfected with a phosphorylation-deficient NR1 construct. Moreover, stimulation of D1 receptors or increase in cyclic AMP levels leads to an increase in cytosolic Ca2+ in the presence of glutamate, but not in the absence of glutamate, indicating the ability of dopamine and cyclic AMP to facilitate NMDA channel activity. The recruitment of the NMDA receptor signal transduction pathway by D1 receptors may provide a general mechanism for gene regulation that is fundamental for mechanisms of drug addiction and long-term memory.