神经科学家发现大脑中重要蛋白质的新结构 诸平 Fig.1 Animation of the four stages of the LeuT transporter put together for a full cycle. Credit: University of Copenhagen 据丹麦 哥本哈根大学 （ University of Copenhagen ）2020年3月6日提供的消息，该大学的研究人员，经过五年的实验，成功地结晶和绘制了一种LeuT的新构型。LeuT是一种细菌蛋白，与大脑的所谓神经递质转运蛋白属于同一家族的蛋白质。图1是哥本哈根大学提供的LeuT转运蛋白的四个阶段的动画组成了一个完整周期。相关研究结果于2020年2月21日已经在《自然通讯》（ Nature Communications ）杂志网站发表—— Kamil Gotfryd , Thomas Boesen , Jonas S. Mortensen , George Khelashvili , Matthias Quick , Daniel S. Terry , Julie W. Missel , Michael V. LeVine , Pontus Gourdon , Scott C. Blanchard , Jonathan A. Javitch , Harel Weinstein , Claus J. Loland , Poul Nissen , Ulrik Gether .X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release. Nature Communications , 2020,Volume11,Articlenumber:1005. DOI: 10.1038/s41467-020-14735-w . Published:21 February 2020 .参与此项研究的除了哥本哈根大学的研究人员之外，还有来自丹麦奥胡斯大学（Aarhus University），美国康奈尔大学（Cornell University）、纽约州精神病研究所（New York State Psychiatric Institute）、圣犹大儿童研究医院(St. Jude Children’s Research Hospital, Memphis)的研究人员。 这些转运蛋白（transporters）是位于细胞膜上的特殊蛋白质。作为一种真空吸尘器，它们可以重新吸收神经细胞在相互发送信号时释放的一些神经递质（neurotransmitters）。一些药物或物质通过阻断转运蛋白，增加神经细胞外部某些神经递质的数量来发挥作用。例如，抗抑郁药抑制神经递质5-羟色胺（serotonin）的再摄取，而麻醉药如可卡因则抑制 神经递质 多巴胺（ neurotransmitter dopamine）的再摄取。 哥本哈根大学 生物医学科学系副教授卡米尔·戈特弗里德（Kamil Gotfryd）说：“转运蛋白对于调节大脑神经元之间的信号传递，并因此平衡整个系统的运作方式极为重要。人不能没有它们。”卡米尔·戈特弗里德是此项研究论文的第一作者，他在该项目研究期间是哥本哈根大学神经科学系的博士后研究者。卡米尔·戈特弗里德补充说：“这项新发现不仅为我们提供了关于复杂转运蛋白的额外基础科学知识。它还具有开发药理学方法的前景，我们可以利用这些方法改变转运蛋白的功能。换句话说，该发现可能会带来更好的药物。 从细菌到人脑 进化的转运蛋白源自最原始的细菌，这些细菌已经发展成为能够从环境中吸收营养（例如氨基酸）以生存的细菌。从那时起，专门的运输工具已经发展到可以完成各种各样的功能。例如，将神经递质 转运 到人脑的神经元中。然而，基本原理是相同的，即转运蛋白的功能是通过交替打开和关闭细胞的内部和外部来实现的。 当一个转运蛋白(transporter)向外打开时，它可能捕获转运蛋白或氨基酸。然后，这种蛋白质利用钠离子来改变其结构，这样它就会向外关闭，而向细胞内部开放，在此释放并吸收被运输的物质。 完整循环 近年来，X射线晶体学使研究人员能够绘制出转运蛋白机制的三个阶段：向外打开，向外关闭和向内打开。为了使循环完整，研究人员早就得出结论，蛋白质一定有一个向内封闭的阶段。然而，由于这种结构是不稳定的，长期以来很难将其冻结，因此无法能够对其进行绘图。 但是现在，经过多次试验，哥本哈根大学的研究人员已经成功地在那个阶段成功地保留了一种用于转运亮氨酸递质的转运蛋白-LeuT。 但是现在，经过多次试验，哥本哈根大学的研究人员已经成功地保留了一种用于传输亮氨酸的转运蛋白。 哥本哈根大学神经科学系教授兼系主任乌尔里克·格瑟（Ulrik Gether）说：“我们已经为此研究了5年，无论我们做什么，我们从来没有得到我们想要的结构。但是突然之间发生了。”真是踏破铁鞋觅无处，得来全不费工夫。他补充说:“事实上，我们的研究可以说是‘缺失这一环’。这种结构已经缺失了，了解转运蛋白（transporter）所经历的整个循环是非常重要的。” 更多发现的关键 乌尔里克·格瑟解释说，解决这个长期存在的谜题的关键部分是转运蛋白的突变，部分相关的亮氨酸（leucine）分子，被稍大一些的苯丙氨酸分子（phenylalanine molecule）所替代。可以这么说，这种组合使转运蛋白在理想的位置上停留了足够长的时间，以便研究人员对其进行提纯、结晶和绘制其结构。 同时，乌尔里克·格瑟解释说，不同类型的转运蛋白之间高度的相似性，使研究人员能够将它们与其他多种神经递质的转运蛋白进行比较。“现在，我们对LeuT有了更多的了解，其结果可能会转移到其他神经递质的其他转运蛋白上。我们相信，我们可以为多巴胺、5-羟色胺和GABA转运蛋白推广和创建更好的模型，这些模型是治疗多动症（ADHD）、抑郁症和癫痫症的靶标。” 据该部门负责人表示，下一步是继续研究在人类神经细胞中发现的转运蛋白。更多信息请注意浏览原文或者相关报道。 Understanding transporter proteins at a single-molecule level Abstract Neurotransmitter:sodium symporters (NSS) are conserved from bacteria to man and serve as targets for drugs, including antidepressants and psychostimulants. Here we report the X-ray structure of the prokaryotic NSS member, LeuT, in a Na + /substrate-bound, inward-facing occluded conformation. To obtain this structure, we were guided by findings from single-molecule fluorescence spectroscopy and molecular dynamics simulations indicating that L -Phe binding and mutation of the conserved N-terminal Trp8 to Ala both promote an inward-facing state. Compared to the outward-facing occluded conformation, our structure reveals a major tilting of the cytoplasmic end of transmembrane segment (TM) 5, which, together with release of the N-terminus but without coupled movement of TM1, opens a wide cavity towards the second Na + binding site. The structure of this key intermediate in the LeuT transport cycle, in the context of other NSS structures, leads to the proposal of an intracellular release mechanism of substrate and ions in NSS proteins.
① 神经发育同时受内外信号调控，很多外周信号影响精神疾病的发生； ② 在焦虑、抑郁、认知缺陷和自闭症中，肠道与大脑联系密切； ③ 在产前和产后，来源于肠道菌群的分子信号等关键环境因素，影响健康且功能健全的大脑发育； ④ 肠道菌群影响血脑屏障、髓鞘、神经形成，小胶质细胞成熟等基础性神经发育进程，调控动物的多种行为； ⑤ 本文系统讨论神经发育与菌群的生物学交集，探讨肠道细菌如何参与神经系统发育和功能并平衡精神健康与疾病。 参考文献： Title： The Central Nervous System and the Gut Microbiome DOI： 10.1016/j.cell.2016.10.027 Abstract： Neurodevelopment is a complex process governed by both intrinsic and extrinsic signals. While historically studied by researching the brain, inputs from the periphery impact many neurological conditions. Indeed, emerging data suggest communication between the gut and the brain in anxiety, depression, cognition, and autism spectrum disorder (ASD). The development of a healthy, functional brain depends on key pre- and post-natal events that integrate environmental cues, such as molecular signals from the gut. These cues largely originate from the microbiome, the consortium of symbiotic bacteria that reside within all animals. Research over the past few years reveals that the gut microbiome plays a role in basic neurogenerative processes such as the formation of the blood-brain barrier, myelination, neurogenesis, and microglia maturation and also modulates many aspects of animal behavior. Herein, we discuss the biological intersection of neurodevelopment and the microbiome and explore the hypothesis that gut bacteria are integral contributors to development and function of the nervous system and to the balance between mental health and disease. All Authors： Gil Sharon,Timothy R Sampson,Daniel H Geschwind,Sarkis K Mazmanian
【最近旅行时在飞机上从 时代杂志 上读到这篇文章，觉得很有意思。它说的是一种部分 成环（通过二硫键）状结构的 多肽，英文是 Oxytocin ,中文翻译成 催产素 ，具有很多神奇 的生理功能，包括亲人之间的安抚功能。详 细可以参 考英文 维基百科 ，或者一个中文医 学 百科网站 。1953年， Vincent du Vigneaud 第一个完成它的人工化学合成，2年后获得了 炸 药奖。下面这篇文章介绍的 是一个有趣的实验：在压力下，跟母亲通电话的儿童，能 够 获得与母亲拥抱过的儿童一 样的安慰效果----因为检测到相似的催生素水平增加。】 Thanks, Mom! http://www.time.com/time/magazine/article/0,9171,1992405,00.html By Tiffany O'Callaghan Monday, Jun. 07, 2010 There are plenty of reasons oxytocin is referred to as the cuddle chemical. Levels of the hormone surge during caresses, and researchers think it evolved as a way to reduce stress and fear of others long enough to enable contact necessary for procreation. It also helps facilitate bonding between mothers and newborns. But for the first time, scientists have found that Mom's innate ability to soothe and to boost oxytocin levels is as powerful whether she's offering a hug in person or consolation over the phone . 【oxytocin，image from http://en.wikipedia.org/wiki/Oxytocin 】 To understand how mothers can influence levels of oxytocin in their children, researchers at the University of Wisconsin-Madison's Child Emotion Lab recruited 61 girls, ages 7 to 12, and placed them in a stressful situation: they had to give an impromptu speech and solve math problems in front of strangers. Afterward, some girls were allowed to seek refuge in their mothers' arms, others talked to Mom on the phone, and the control group watched an emotion-neutral film ( March of the Penguins ) that bored many participants to sleep. The results, published in May in the biological-sciences journal Proceedings of the Royal Society B , showed that oxytocin levels jumped almost exactly as much in girls who were comforted in person as they did in girls who'd been calmed long distance. The findings add to a growing body of research on the impact of oxytocin , which has been shown to promote such qualities as generosity and empathy. Leslie Seltzer , the biological anthropologist who led the study, suggests an evolutionary reason for the soothing power of Mom's voice. When faced with a threat say, members of a rival tribe men could choose to fight or take flight, but women's options were complicated by having little ones in tow. Fleeing might expose the children to more danger. That's why, Seltzer speculates, women may have developed the ability to use social bonds to tend and befriend to diminish stress either by touching or by talking. Seltzer's next study: to see if Mom can send some oxytocin love by instant message . 附：原始文献 http://rspb.royalsocietypublishing.org/content/early/2010/05/06/rspb.2010.0567.abstract Social vocalizations can release oxytocin in humans Leslie J. Seltzer 1 , * , Toni E. Ziegler 2 and Seth D. Pollak 1 Abstract Vocalizations are important components of social behaviour in many vertebrate species, including our own. Less well-understood are the hormonal mechanisms involved in response to vocal cues, and how these systems may influence the course of behavioural evolution. The neurohormone oxytocin (OT) partly governs a number of biological and social processes critical to fitness, such as attachment between mothers and their young, and suppression of the stress response after contact with trusted conspecfics. Rodent studies suggest that OT's release is contingent upon direct tactile contact with such individuals, but we hypothesized that vocalizations might be capable of producing the same effect. To test our hypothesis, we chose human motherdaughter dyads and applied a social stressor to the children, following which we randomly assigned participants into complete contact, speech-only or no-contact conditions. Children receiving a full complement of comfort including physical, vocal and non-verbal contact showed the highest levels of OT and the swiftest return to baseline of a biological marker of stress (salivary cortisol), but a strikingly similar hormonal profile emerged in children comforted solely by their mother's voice. Our results suggest that vocalizations may be as important as touch to the neuroendocrine regulation of social bonding in our species.
标签: 神经递质
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