Protein Kinase DI-Dependent Phosphorylation of Dopamine DI Receptor Regulates Cocaine-Induced Behavioral Responses
Protein Kinase DI-Dependent Phosphorylation of Dopamine DI Receptor Regulates Cocaine-Induced Behavioral Responses
复制标题
多巴胺 DI 受体的蛋白激酶 DI 依赖性磷酸化调节可卡因诱导的行为反应
DOI：
10.1038/npp.2013.341
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发表时间：
2014-04-01
影响因子：
7.6
通讯作者：
Wang, Yun
中科院分区：
文献类型：
--
作者：
Wang, Ning;Su, Ping;Wang, Yun
The dopamine (DA) DI receptor (DIR) is critically involved in reward and drug addiction. Phosphorylation-mediated desensitization or internalization of DIR has been extensively investigated. However, the potential for upregulation of DIR function through phosphorylation remains to be determined. Here we report that acute cocaine exposure induces protein kinase DI (PKD I) activation in the rat striatum, and knockdown of PKDI in the rat dorsal striatum attenuates cocaine-induced locomotor hyperactivity. Moreover, PKD I -mediated phosphorylation of serine 421 (S42I) of DIR promotes surface localization of D1R and enhances downstream extracellular signal-regulated kinase signaling in DIR-transfected HEK 293 cells. Importantly, injection of the peptide Tat-S421, an engineered Tat fusion-peptide targeting S42I (Tat-S421), into the rat dorsal striatum inhibits cocaine-induced locomotor hyperactivity and injection of Tat-S421 into the rat hippocampus or the shell of the nucleus accumbens (NAc) also inhibits cocaine-induced conditioned place preference (CPP). However, injection of Tat-S421 into the rat NAc shell does not establish CPP by itself and injection of Tat-S421 into the hippocampus does not influence spatial learning and memory. Thus, targeting S421 of DIR represents a promising strategy for the development of pharmacotherapeutic treatments for drug addiction and other disorders that result from DA imbalances.
