A novel role for ecdysone in Drosophila conditioned behavior: linking GPCR-mediated non-canonical steroid action to cAMP signaling in the adult brain.
A novel role for ecdysone in Drosophila conditioned behavior: linking GPCR-mediated non-canonical steroid action to cAMP signaling in the adult brain.
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DOI：
10.1371/journal.pgen.1003843
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Kitamoto T
中科院分区：
文献类型：
--
作者：
Ishimoto H;Wang Z;Rao Y;Wu CF;Kitamoto T
类固醇激素的生物学作用主要由其同源核受体介导，其充当类固醇依赖性转录因子。然而，类固醇也可以通过快速调节细胞内信号级联来执行其功能，并且独立于转录调控。尽管这种“非基因组”类固醇作用的潜在意义，但它们的生物学作用和潜在的分子机制尚未得到很好的理解，特别是关于它们对行为调节的影响。果蝇体内的主要类固醇激素是20-羟基蜕皮激素（20 E），它通过核蜕皮激素受体在发育过程中发挥各种关键作用。在这里，我们报告说，DopEcR，蜕皮激素的G-蛋白偶联受体，参与活动和经验依赖性的可塑性的成人中枢神经系统。值得注意的是，求偶记忆缺陷的芜菁甘蓝（钙/钙调素响应性腺苷酸环化酶）突变体被救出DopEcR过表达或急性20 E喂养，而记忆缺陷的dunce（cAMP特异性磷酸二酯酶）突变体被抵消时，功能丧失DopEcR突变被引入。通过增强DopEcR介导的蜕皮激素信号传导，抑制多巴胺合成引起的记忆缺陷也得到了恢复，并且救援和表型实验表明，蘑菇体（MB）-果蝇学习和记忆的大脑中心区域-对于DopEcR依赖的求爱记忆处理至关重要。与这一发现相一致，急性20 E喂养诱导了MB中cAMP水平的快速，DopEcR依赖性增加。我们的多学科的方法表明，DopEcR介导的20 E的非规范的行动，并迅速调节成人条件行为通过cAMP信号，这是普遍重要的神经可塑性。这项研究为类固醇的非基因组作用提供了新的见解，并为类固醇行为控制的关键机制的遗传研究开辟了新的途径。大脑是类固醇激素的一个重要靶点，类固醇激素控制着各种神经生物学过程，对行为的调节至关重要。这些激素的一些作用涉及基因表达的变化，因此在几小时甚至几天的过程中缓慢出现。对类固醇的其他反应迅速发生，并且不依赖于转录调控。它们的功能和作用机制知之甚少，特别是在类固醇介导的行为控制方面。在这里，我们显示，使用遗传模式生物果蝇（果蝇），一种非常规的，膜结合的蜕皮激素蜕皮激素受体在成人大脑中传输一种新形式的类固醇信号。我们的研究表明，这种新形式的类固醇信号传导与经典的“记忆基因”有着强大的界面，这些基因编码所谓的cAMP信号传导途径的中心成分，这对神经元和行为可塑性具有普遍重要性。这些发现强调了类固醇信号在记忆处理中的重要性，并为行为调节中快速，非常规类固醇信号的遗传分析提供了基础。
The biological actions of steroid hormones are mediated primarily by their cognate nuclear receptors, which serve as steroid-dependent transcription factors. However, steroids can also execute their functions by modulating intracellular signaling cascades rapidly and independently of transcriptional regulation. Despite the potential significance of such “non-genomic” steroid actions, their biological roles and the underlying molecular mechanisms are not well understood, particularly with regard to their effects on behavioral regulation. The major steroid hormone in the fruit fly Drosophila is 20-hydroxy-ecdysone (20E), which plays a variety of pivotal roles during development via the nuclear ecdysone receptors. Here we report that DopEcR, a G-protein coupled receptor for ecdysteroids, is involved in activity- and experience-dependent plasticity of the adult central nervous system. Remarkably, a courtship memory defect in rutabaga (Ca2+/calmodulin-responsive adenylate cyclase) mutants was rescued by DopEcR overexpression or acute 20E feeding, whereas a memory defect in dunce (cAMP-specific phosphodiestrase) mutants was counteracted when a loss-of-function DopEcR mutation was introduced. A memory defect caused by suppressing dopamine synthesis was also restored through enhanced DopEcR-mediated ecdysone signaling, and rescue and phenocopy experiments revealed that the mushroom body (MB)—a brain region central to learning and memory in Drosophila—is critical for the DopEcR-dependent processing of courtship memory. Consistent with this finding, acute 20E feeding induced a rapid, DopEcR-dependent increase in cAMP levels in the MB. Our multidisciplinary approach demonstrates that DopEcR mediates the non-canonical actions of 20E and rapidly modulates adult conditioned behavior through cAMP signaling, which is universally important for neural plasticity. This study provides novel insights into non-genomic actions of steroids, and opens a new avenue for genetic investigation into an underappreciated mechanism critical to behavioral control by steroids. The brain is a prominent target of steroid hormones, which control a variety of neurobiological processes and are critical to the regulation of behavior. Some effects of these hormones involve changes in gene expression and thus emerge slowly, over the course of hours or even days. Other responses to steroids occur rapidly and are independent of transcriptional regulation. Their functions and mechanisms of action are poorly understood, particularly in the context of steroid-mediated control of behavior. Here we show, using the genetic model organism Drosophila melanogaster (the fruit fly), that an unconventional, membrane-bound receptor for the molting hormone ecdysone transmits a novel form of steroid signaling in the adult brain. Our study shows that this novel form of steroid signaling has a robust interface with the classical “memory genes” that encode central components of the so-called cAMP signaling pathway, which is universally important for neuronal and behavioral plasticity. These findings underscore the significance of steroid signaling in memory processing, and provide a foundation for the genetic analysis of rapid, unconventional steroid signaling in behavioral regulation.
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影响因子：
2
作者：
Engel, JE;Xie, XJ;Wu, CF
通讯作者：
Wu, CF
影响因子：
3.3
作者：
Ishimoto, Hiroshi;Kitamoto, Toshihiro
通讯作者：
Kitamoto, Toshihiro
影响因子：
4.1
作者：
Gilbert, LI
通讯作者：
Gilbert, LI
影响因子：
2.5
作者：
Cooper, RL;Ruffner, ME
通讯作者：
Ruffner, ME
DOI：
10.1242/jeb.014878
发表时间：
2008-08
期刊：
The Journal of experimental biology
影响因子：
--
作者：
Flatt T;Heyland A;Rus F;Porpiglia E;Sherlock C;Yamamoto R;Garbuzov A;Palli SR;Tatar M;Silverman N
通讯作者：
Silverman N