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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice.
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Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice.

机译：同时缺乏多巴胺D1和D2受体介导的信号传导对小鼠具有致死性。

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摘要

Dopamine (DA) controls a wide variety of physiological functions in the central nervous system as well as in the neuroendocrine and gastrointestinal systems. DA signaling is mediated by five cloned receptors named D1-D5. Knockout mouse models for the five receptors have been generated, and, albeit impaired for some important DA-mediated functions, they are viable and can reproduce. D1 and D2 receptors are the most abundant and widely expressed DA receptors. Cooperative/synergistic effects mediated by these receptors have been suggested, in particular, in the control of motor behaviors. To analyze the extent of such interrelationship, we have generated double D1/D2 receptor mutants. Interestingly, in contrast to single knockouts, we found that concurrent ablation of the D1 and D2 receptors is lethal during the second or third week after birth. This dramatic phenotype is likely to be related to altered feeding behavior and dysfunction of the gastrointestinal system, especially because major anatomical changes were not identified in the brain. Similarly, in the absence of functional D1, heterozygous D2 mutants (D1r(-/-);D2r(+/-)) showed severe growth retardation and did not survive their postweaning period. The analysis of motor behavior in D1r/D2r compound mutants showed that loss of D2-mediated functions reduces motor abilities, whereas the effect of D1r ablation on locomotion strongly depends on the experimental paradigms used. These studies highlight the interrelationship between D1 and D2 receptor-mediated control of motor activity, food intake, and gastrointestinal functions, which has been elusive in the single-gene ablation studies.
机译：多巴胺（DA）控制中枢神经系统以及神经内分泌和胃肠系统的多种生理功能。 DA信号由五个名为D1-D5的克隆受体介导。已经生成了五种受体的敲除小鼠模型，尽管某些重要的DA介导的功能受损，但它们是可行的并且可以繁殖。 D1和D2受体是最丰富和表达最广泛的DA受体。已经提出了由这些受体介导的协同/协同作用，特别是在运动行为的控制中。为了分析这种相互关系的程度，我们产生了双D1 / D2受体突变体。有趣的是，与单敲除相比，我们发现在出生后第二或第三周同时消融D1和D2受体是致命的。这种戏剧性的表型可能与进食行为的改变和胃肠系统的功能障碍有关，特别是因为在大脑中未发现主要的解剖学变化。同样，在没有功能性D1的情况下，杂合D2突变体（D1r（-/-）; D2r（+/-））表现出严重的生长迟缓，并且不能在断奶后存活。 D1r / D2r复合突变体的运动行为分析表明，D2介导的功能丧失会降低运动能力，而D1r消融对运动的影响在很大程度上取决于所使用的实验范式。这些研究强调了D1和D2受体介导的运动活动，食物摄入和胃肠功能之间的相互关系，这在单基因消融研究中一直难以捉摸。

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