Signaling mediated by the dopamine D2 receptor potentiates circadian regulation by CLOCK:BMAL1.
Signaling mediated by the dopamine D2 receptor potentiates circadian regulation by CLOCK:BMAL1.
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DOI：
10.1073/pnas.0510691103
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发表时间：
2006-04
影响因子：
11.1
通讯作者：
I. Yujnovsky;J. Hirayama;M. Doi;E. Borrelli;P. Sassone-Corsi
中科院分区：
文献类型：
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作者：
I. Yujnovsky;J. Hirayama;M. Doi;E. Borrelli;P. Sassone-Corsi
环境信号调节多种细胞内通路，其信号通过构成生物钟的分子机制整合。尽管昼夜节律机制的基本齿轮已被阐明，但对调节它的信号系统知之甚少。在这里，我们报道了多巴胺D2受体（D2R）介导的信号传导增强了CLOCK:BMAL1复合物的转录能力。这种效应涉及丝裂原激活的蛋白激酶转导级联，并与d2r诱导的转录共激活因子cAMP-responsive element-binding protein （CREB）结合蛋白的募集和磷酸化增加有关。重要的是，CLOCK: bmal1依赖性激活和mPer1基因转录的光诱导性在d2r缺失小鼠的视网膜中被严重抑制。由于多巴胺是视网膜中主要的儿茶酚胺，是神经对光的适应中枢，我们的研究结果在光输入、多巴胺信号和分子时钟机制之间建立了生理联系。
Environmental cues modulate a variety of intracellular pathways whose signaling is integrated by the molecular mechanism that constitutes the circadian clock. Although the essential gears of the circadian machinery have been elucidated, very little is known about the signaling systems regulating it. Here, we report that signaling mediated by the dopamine D2 receptor (D2R) enhances the transcriptional capacity of the CLOCK:BMAL1 complex. This effect involves the mitogen-activated protein kinase transduction cascade and is associated with a D2R-induced increase in the recruiting and phosphorylation of the transcriptional coactivator cAMP-responsive element-binding protein (CREB) binding protein. Importantly, CLOCK:BMAL1-dependent activation and light-inducibility of mPer1 gene transcription is drastically dampened in retinas of D2R-null mice. Because dopamine is the major catecholamine in the retina, central for the neural adaptation to light, our findings establish a physiological link among photic input, dopamine signaling, and the molecular clock machinery.