Schizophrenia, amphetamine-induced sensitized state and acute amphetamine exposure all show a common alteration: increased dopamine D2 receptor dimerization.
Schizophrenia, amphetamine-induced sensitized state and acute amphetamine exposure all show a common alteration: increased dopamine D2 receptor dimerization.
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DOI：
10.1186/1756-6606-3-25
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发表时间：
2010-09-02
期刊：
影响因子：
3.6
通讯作者：
Liu F
中科院分区：
文献类型：
--
作者：
Wang M;Pei L;Fletcher PJ;Kapur S;Seeman P;Liu F
所有抗精神病药物均通过多巴胺 D2 受体 (D2R) 发挥作用，这表明 D2R 在精神病中发挥着关键作用；然而，几乎没有证据表明 D2R 的受体数量或药理学性质发生了变化。最近的数据表明，D2R 在体外和体内形成二聚体，我们假设精神分裂症以及精神分裂症的临床前模型将表现出 D2R 的二聚体改变，即使 D2R 的总数未改变。我们使用蛋白质印迹法测量了精神分裂症患者中 D2Rs 二聚体和单体的表达，然后测量了表现出安非他明诱导的敏化状态 (AISS) 的大鼠纹状体组织中的 D2Rs 二聚体和单体的表达。我们通过免疫共沉淀进一步检查了 D2R 和多巴胺转运蛋白 (DAT) 之间的相互作用，并通过配体结合测定在有或没有急性安非他明预处理的大鼠纹状体切片中测量多巴胺 D2High 受体的表达。我们观察到精神分裂症患者死后纹状体组织中 D2Rs 二聚体的表达显着增强 (277.7 ± 33.6%)，而 D2Rs 单体的表达显着降低。我们发现安非他明促进 AISS 大鼠纹状体和大鼠纹状体神经元中 D2Rs 二聚化。此外，安非他明诱导的 D2Rs 二聚化可能与 D2R-DAT 蛋白质-蛋白质相互作用有关，作为干扰肽破坏 D2R-DAT 偶联，阻断安非他明诱导的 D2Rs 二聚化上调。鉴于安非他明会诱发精神病，并且 AISS 大鼠是一种广泛接受的精神病动物模型，我们的数据表明 D2R 二聚化可能在精神分裂症的病理生理学中很重要，并且可能是新型抗精神病药物的一个有前途的新靶点。
All antipsychotics work via dopamine D2 receptors (D2Rs), suggesting a critical role for D2Rs in psychosis; however, there is little evidence for a change in receptor number or pharmacological nature of D2Rs. Recent data suggest that D2Rs form dimers in-vitro and in-vivo, and we hypothesized that schizophrenia, as well as preclinical models of schizophrenia, would demonstrate altered dimerization of D2Rs, even though the overall number of D2Rs was unaltered. We measured the expression of D2Rs dimers and monomers in patients with schizophrenia using Western blots, and then in striatal tissue from rats exhibiting the amphetamine-induced sensitized state (AISS). We further examined the interaction between D2Rs and the dopamine transporter (DAT) by co-immunoprecipitation, and measured the expression of dopamine D2High receptors with ligand binding assays in rat striatum slices with or without acute amphetamine pre-treatment. We observed significantly enhanced expression of D2Rs dimers (277.7 ± 33.6%) and decreased expression of D2Rs monomers in post-mortem striatal tissue of schizophrenia patients. We found that amphetamine facilitated D2Rs dimerization in both the striatum of AISS rats and in rat striatal neurons. Furthermore, amphetamine-induced D2Rs dimerization may be associated with the D2R-DAT protein-protein interaction as an interfering peptide that disrupts the D2R-DAT coupling, blocked amphetamine-induced up-regulation of D2Rs dimerization. Given the fact that amphetamine induces psychosis and that the AISS rat is a widely accepted animal model of psychosis, our data suggest that D2R dimerization may be important in the pathophysiology of schizophrenia and may be a promising new target for novel antipsychotic drugs.
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影响因子：
3.6
作者：
Li, M;Bermak, JC;Zhou, QY
通讯作者：
Zhou, QY
影响因子：
64.5
作者：
Lee, FJS;Xue, S;Liu, F
通讯作者：
Liu, F
影响因子：
4.8
作者：
Armstrong, D;Strange, PG
通讯作者：
Strange, PG
影响因子：
4.7
作者：
Kim OJ;Ariano MA;Namkung Y;Marinec P;Kim E;Han J;Sibley DR
通讯作者：
Sibley DR
DOI：
10.1073/pnas.0604049104
发表时间：
2007-01-09
影响因子：
11.1
作者：
Rashid, Asim J.;So, Christopher H.;George, Susan R.
通讯作者：
George, Susan R.