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初级纤毛增强促性腺激素释放激素神经元上的 kisspeptin 受体信号传导。

Primary cilia enhance kisspeptin receptor signaling on gonadotropin-releasing hormone neurons.

机构信息

Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, OH 43210;

Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210;

出版信息

Proc Natl Acad Sci U S A. 2014 Jul 15;111(28):10335-40. doi: 10.1073/pnas.1403286111. Epub 2014 Jun 30.

Abstract

Most central neurons in the mammalian brain possess an appendage called a primary cilium that projects from the soma into the extracellular space. The importance of these organelles is highlighted by the fact that primary cilia dysfunction is associated with numerous neuropathologies, including hyperphagia-induced obesity, hypogonadism, and learning and memory deficits. Neuronal cilia are enriched for signaling molecules, including certain G protein-coupled receptors (GPCRs), suggesting that neuronal cilia sense and respond to neuromodulators in the extracellular space. However, the impact of cilia on signaling to central neurons has never been demonstrated. Here, we show that the kisspeptin receptor (Kiss1r), a GPCR that is activated by kisspeptin to regulate the onset of puberty and adult reproductive function, is enriched in cilia projecting from mouse gonadotropin-releasing hormone (GnRH) neurons. Interestingly, GnRH neurons in adult animals are multiciliated and the percentage of GnRH neurons possessing multiple Kiss1r-positive cilia increases during postnatal development in a progression that correlates with sexual maturation. Remarkably, disruption of cilia selectively on GnRH neurons leads to a significant reduction in kisspeptin-mediated GnRH neuronal activity. To our knowledge, this result is the first demonstration of cilia disruption affecting central neuronal activity and highlights the importance of cilia for proper GPCR signaling.

摘要

哺乳动物大脑中的大多数中枢神经元都有一个叫做初级纤毛的附属物,它从体细胞伸向细胞外空间。这些细胞器的重要性体现在初级纤毛功能障碍与许多神经病理学有关,包括摄食过多引起的肥胖、性腺功能减退以及学习和记忆缺陷。神经元纤毛富含信号分子,包括某些 G 蛋白偶联受体 (GPCR),这表明神经元纤毛可以感知细胞外空间中的神经调质并作出反应。然而,纤毛对中枢神经元信号传递的影响尚未得到证实。在这里,我们表明,促性腺激素释放激素 (GnRH) 神经元中存在由 kisspeptin 激活的 G 蛋白偶联受体 (Kiss1r),该受体丰富于从体细胞伸出的纤毛中。有趣的是,成年动物中的 GnRH 神经元是多纤毛的,并且在性成熟过程中,具有多个 Kiss1r 阳性纤毛的 GnRH 神经元的百分比增加。值得注意的是,选择性破坏 GnRH 神经元上的纤毛会导致 kisspeptin 介导的 GnRH 神经元活性显著降低。据我们所知,这一结果首次证明了纤毛破坏会影响中枢神经元的活动,并强调了纤毛对于适当的 GPCR 信号传递的重要性。

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