Circadian-related heteromerization of adrenergic and dopamine D₄ receptors modulates melatonin synthesis and release in the pineal gland.
Circadian-related heteromerization of adrenergic and dopamine D₄ receptors modulates melatonin synthesis and release in the pineal gland.
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DOI：
10.1371/journal.pbio.1001347
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发表时间：
2012
期刊：
影响因子：
9.8
通讯作者：
McCormick PJ
中科院分区：
文献类型：
--
作者：
González S;Moreno-Delgado D;Moreno E;Pérez-Capote K;Franco R;Mallol J;Cortés A;Casadó V;Lluís C;Ortiz J;Ferré S;Canela E;McCormick PJ
多巴胺和肾上腺素能受体复合物在昼夜节律调节的周期下形成，并直接调节松果体的褪黑激素合成和释放。松果体的作用是将视网膜编码的昼夜节律转换成激素信号，这些激素信号以5-羟色胺和褪黑激素合成和释放的形式传递到神经系统的其余部分。在这里，我们描述了松果体的褪黑激素和5-羟色胺的生产是由肾上腺素和多巴胺D4受体的昼夜节律相关的异聚化调节。多巴胺通过α1 B-D4和β1-D4受体异聚体抑制肾上腺素能受体信号传导，阻断肾上腺素能受体配体诱导的褪黑激素合成。当D4不表达时，在一天中的小时未观察到这种抑制。这些数据为多巴胺功能提供了一个新的视角，并构成了昼夜节律控制受体异聚体的第一个例子。肾上腺素能受体和多巴胺D4受体之间的意外异聚化为多巴胺形式的神经元激素系统提供了反馈机制，以控制昼夜节律输入。动物对光明和黑暗的循环做出反应，包括睡眠、进食、体温变化和其他生物功能。松果体将从视网膜接收到的这些光信号翻译成身体其他部分可以理解的语言，通过有节奏地合成和释放褪黑激素来响应光和暗周期。这个过程是由肾上腺素能受体控制的。该系统的一个令人印象深刻和神秘的方面是有节奏的褪黑激素产生和/或降解的快速能力，以响应周期的变化。在这项研究中，我们证明了这种反应的一部分是由于肾上腺素能受体α1B或β1与D4多巴胺受体之间形成受体-受体复合物（异聚体）。在转染细胞和离体组织中使用生物化学和生物物理方法，我们表明多巴胺，一种神经递质，通过这些异聚体抑制肾上腺素能受体信号传导。这种抑制导致松果体的褪黑激素产生急剧减少。我们假设，这些异聚体提供了一个快速的反馈机制，神经元激素系统调节昼夜节律控制的输出。
Dopamine and adrenergic receptor complexes form under a circadian-regulated cycle and directly modulate melatonin synthesis and release from the pineal gland. The role of the pineal gland is to translate the rhythmic cycles of night and day encoded by the retina into hormonal signals that are transmitted to the rest of the neuronal system in the form of serotonin and melatonin synthesis and release. Here we describe that the production of both melatonin and serotonin by the pineal gland is regulated by a circadian-related heteromerization of adrenergic and dopamine D4 receptors. Through α1 B-D4 and β1-D4 receptor heteromers dopamine inhibits adrenergic receptor signaling and blocks the synthesis of melatonin induced by adrenergic receptor ligands. This inhibition was not observed at hours of the day when D4 was not expressed. These data provide a new perspective on dopamine function and constitute the first example of a circadian-controlled receptor heteromer. The unanticipated heteromerization between adrenergic and dopamine D4 receptors provides a feedback mechanism for the neuronal hormone system in the form of dopamine to control circadian inputs. Animals respond to cycles of light and dark with patterns in sleeping, feeding, body temperature alterations, and other biological functions. The pineal gland translates these light signals received from the retina into a language understandable to the rest of the body through the rhythmic synthesis and release of melatonin in response to the light and dark cycle. This process is controlled by adrenergic receptors. One impressive and mysterious aspect of the system is the rapid ability of rhythmic melatonin production and/or degradation to respond to changes in the cycle. In this study, we demonstrate that part of this response is due to the formation of receptor-receptor complexes (heteromers) between the adrenergic receptors α1B or β1 and the D4 dopamine receptor. Using both biochemical and biophysical methods in transfected cells and in ex vivo tissue we show that dopamine, a neurotransmitter, inhibits adrenergic receptor signaling through these heteromers. This inhibition causes a dramatic decrease in melatonin production of the pineal gland. We postulate that these heteromers provide a rapid feedback mechanism for the neuronal hormone system to modulate circadian-controlled outputs.
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影响因子：
4.8
作者：
George, SR;Fan, T;O'Dowd, BF
通讯作者：
O'Dowd, BF
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