Dopamine D1-histamine H3 Receptor Heteromers Provide a Selective Link to MAPK Signaling in GABAergic Neurons of the Direct Striatal Pathway
Dopamine D1-histamine H3 Receptor Heteromers Provide a Selective Link to MAPK Signaling in GABAergic Neurons of the Direct Striatal Pathway
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DOI：
10.1074/jbc.m110.161489
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发表时间：
2011-02-18
影响因子：
4.8
通讯作者：
Franco, Rafael
中科院分区：
文献类型：
--
作者：
Moreno, Estefana;Hoffmann, Hanne;Franco, Rafael
以前，使用人工细胞系统，我们确定了多巴胺D-1或D-2受体和组胺H-3受体之间的受体异聚体。此外，我们证明了多巴胺D-1受体-组胺H-3受体异聚体的两个生化特性。我们现在已经扩展了这项工作，表明多巴胺D-1受体-组胺H-3受体异聚体存在于大脑中，并提供了一个新的MAPK通路和GABA能神经元之间的直接纹状体传出通路。使用以前确定的生化特征，我们发现，H-3受体激活刺激p44和p42细胞外信号调节的MAPK（ERK 1/2）磷酸化的能力，只观察到在纹状体切片的小鼠表达D-1受体，但不是在D-1受体缺陷小鼠。另一方面，D-1和H-3受体拮抗剂阻断由D-1或H-3受体激动剂诱导的MAPK活化的能力也在纹状体切片中发现。总之，这些数据表明D-1-H-3受体复合物在纹状体中的发生，更重要的是，H-3受体激动剂诱导的ERK 1/2磷酸化在纹状体切片中是由D-1-H-3受体异聚体介导的。此外，H-3受体介导的磷酸化ERK 1/2标记与含D-1受体的纹状体神经元共分布，但不与含D-2受体的纹状体神经元共分布。这些结果表明，D-1-H-3受体异聚体作为处理器整合多巴胺和组胺相关的信号参与控制纹状体神经元的直接纹状体通路的功能。
Previously, using artificial cell systems, we identified receptor heteromers between the dopamine D-1 or D-2 receptors and the histamine H-3 receptor. In addition, we demonstrated two biochemical characteristics of the dopamine D-1 receptor-histamine H-3 receptor heteromer. We have now extended this work to show the dopamine D-1 receptor-histamine H-3 receptor heteromer exists in the brain and serves to provide a novel link between the MAPK pathway and the GABAergic neurons in the direct striatal efferent pathway. Using the biochemical characteristics identified previously, we found that the ability of H-3 receptor activation to stimulate p44 and p42 extracellular signal-regulated MAPK (ERK 1/2) phosphorylation was only observed in striatal slices of mice expressing D-1 receptors but not in D-1 receptor-deficient mice. On the other hand, the ability of both D-1 and H-3 receptor antagonists to block MAPK activation induced by either D-1 or H-3 receptor agonists was also found in striatal slices. Taken together, these data indicate the occurrence of D-1-H-3 receptor complexes in the striatum and, more importantly, that H-3 receptor agonist-induced ERK 1/2 phosphorylation in striatal slices is mediated by D-1-H-3 receptor heteromers. Moreover, H-3 receptor-mediated phospho-ERK 1/2 labeling co-distributed with D-1 receptor-containing but not with D-2 receptor-containing striatal neurons. These results indicate that D-1-H-3 receptor heteromers work as processors integrating dopamine-and histamine-related signals involved in controlling the function of striatal neurons of the direct striatal pathway.