Modulation of D2R-NR2B interactions in response to cocaine
Modulation of D2R-NR2B interactions in response to cocaine
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DOI：
10.1016/j.neuron.2006.10.011
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发表时间：
2006-12-07
期刊：
影响因子：
16.2
通讯作者：
Wang, John Q.
中科院分区：
文献类型：
--
作者：
Liu, Xian-Yu;Chu, Xiang-Ping;Wang, John Q.
新纹状体中的多巴胺-谷氨酸相互作用决定了精神兴奋作用，但潜在的分子机制仍然难以捉摸。在这里，我们发现可卡因刺激的多巴胺增强了体内新纹状体中多巴胺 D2 受体 (D2R) 和 NMDA 受体 NR2B 亚基之间异质受体复合物的形成。 D2R-NR2B 相互作用是直接的，发生在兴奋性突触的受限突触后密度微区中。增强的 D2R-NR2B 相互作用会破坏 Ca2+/钙调蛋白依赖性蛋白激酶 H (CaMKII) 与 NR2B 的关联，减少 CaMKII 敏感位点 (Ser1303) 的 NR2B 磷酸化，并抑制中等大小纹状体神经元中 NMDA 受体介导的电流。此外，受调节的 D2R-NR2B 相互作用对于构建对可卡因的行为反应至关重要。我们的研究结果揭示了体内纹状体神经元中直接且动态的 D2R-NR2B 相互作用。这种受体水平上的多巴胺-谷氨酸整合可能负责协同抑制基底神经节中 D2R 介导的回路并实现精神兴奋剂的刺激作用。
Dopamine-glutamate interactions in the neostriatum determine psychostimulant action, but the underlying molecular mechanisms remain elusive. Here we found that dopamine stimulation by cocaine enhances a heteroreceptor complex formation between dopamine D2 receptors (D2R) and NMDA receptor NR2B subunits in the neostriatum in vivo. The D2R-NR2B interaction is direct and occurs in the confined postsynaptic density microdomain of excitatory synapses. The enhanced D2R-NR2B interaction disrupts the association of Ca2+/ calmodulin-dependent protein kinase H (CaMKII) with NR2B, reduces NR2B phosphorylation at a CaMKII-sensitive site (Ser1303), and inhibits NMDA receptor-mediated currents in medium-sized striatal neurons. Furthermore, the regulated D2R-NR2B interaction is critical for constructing behavioral responsiveness to cocaine. Our findings here uncover a direct and dynamic D2R-NR2B interaction in striatal neurons in vivo. This type of dopamine-glutamate integration at the receptor level may be responsible for synergistically inhibiting the D2R-mediated circuits in the basal ganglia and fulfilling the stimulative effect of psychostimulants.