Melatonin affects nuclear orphan receptors mRNA in the rat suprachiasmatic nuclei
Melatonin affects nuclear orphan receptors mRNA in the rat suprachiasmatic nuclei
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DOI：
10.1016/j.neuroscience.2006.09.030
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发表时间：
2007-01-19
期刊：
影响因子：
3.3
通讯作者：
Gauer, F.
中科院分区：
文献类型：
--
作者：
Agez, L.;Laurent, V.;Gauer, F.
松果体激素褪黑激素的夜间合成反馈到视交叉上核（SCN），中央生物钟。事实上，每天给自由奔跑的大鼠注射褪黑激素可以使它们的运动活动延长到24小时。然而，这种激素的生物钟效应的分子机制知之甚少。内源性昼夜节律机制涉及不同基因（特别是周期（Per）1-3，Clock，Bmal 1，隐花色素（Cry）1-2）的正和负转录反馈环。虽然CLOCK：BMAL 1异二聚体激活PER和cry基因的节律性转录，但PER和CRY蛋白抑制CLOCK：BMAL 1复合物。在以前的研究中，我们观察到，在主观一天结束时注射褪黑激素对SCN昼夜节律活动的即时重置效应并不直接涉及上述时钟基因。最近，核孤儿受体（NORs）已被提出作为分子钟的调节环之间的功能联系。这些NORs与视黄酸受体相关孤儿受体反应元件（RORE）结构域结合，并激活（ROR α）或抑制（REV-ERB α）bmal 1表达。在这项研究中，我们调查是否褪黑激素发挥其生物钟效应，通过这些转录因子的转录调控。我们监测误差α，误差β和rev-erb α信使RNA（mRNA）的表达水平，定量原位杂交，到36小时后，褪黑激素注射在昼夜节律时间（CT）11.5。结果清楚地表明，虽然rora不受褪黑激素的影响，但在注射后的第一个小时内，该激素部分阻止了对照动物中观察到的ror β mRNA表达的下降。主要结果是，在褪黑激素给药后的第一个主观夜晚，褪黑激素治疗动物的rev-erba mRNA表达节律为1.3 +/- 0.8-h相位提前。此外，在注射褪黑激素后的第二个主观夜晚，bmal 1 mRNA的表达发生了1.9 +/- 0.9-h的相移。这些结果清楚地表明，NOR基因可能是褪黑激素的生物钟作用与分子生物钟核心之间的联系。(c)2006年IBRO。由爱思唯尔有限公司出版。保留所有权利。
The pineal hormone melatonin nocturnal synthesis feeds back on the suprachiasmatic nuclei (SCN), the central circadian clock. Indeed, daily melatonin injections in free-running rats resynchronize their locomotor activity to 24 h. However, the molecular mechanisms underlying this chronobiotic effect of the hormone are poorly understood. The endogenous circadian machinery involves Positive and negative transcriptional feedback loops implicating different genes (particularly period (Per) 1-3, Clock, Bmal1, cryptochrome (Cry) 1-2). While CLOCK:BMAL1 heterodimer activates the rhythmic transcription of per and cry genes, the PER and CRY proteins inhibit the CLOCK:BMAL1 complex. In previous studies, we observed that the immediate resetting effect of a melatonin injection at the end of the subjective day on the SCN circadian activity did not directly involve the above-mentioned clock genes. Recently, nuclear orphan receptors (NORs) have been presented as functional links between the regulatory loops of the molecular clock. These NORs bind to a retinoic acid receptor-related orphan receptor response element (RORE) domain and activate (ROR alpha) or repress (REV-ERB alpha) bmal1 expression. In this study, we investigated whether melatonin exerts its chronobiotic effects through transcriptional regulation of these transcription factors. We monitored ror alpha, ror beta and rev-erb alpha messenger RNA (mRNA) expression levels by quantitative in situ hybridization, up to 36 h following a melatonin injection at circadian time (CT) 11.5. Results clearly showed that, while rora was not affected by melatonin, the hormone partially prevented the decrease of the ror beta mRNA expression observed in control animals during the first hours following the injection. The major result is that the rev-erba mRNA expression rhythm was 1.3 +/- 0.8-h phase-advanced in melatonin-treated animals during the first subjective night following the melatonin administration. Moreover, the bmal1 mRNA expression was 1.9 +/- 0.9-h phase-shifted in the second subjective night following the melatonin injection. These results clearly suggest that the NOR genes could be the link between the chronobiotic action of melatonin and the core of the molecular circadian clock. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.