An unexpected role of glutamate receptors in the peripheral nervous system

感知环境温度的能力对生命来说是必不可少的。分子热传感器是一个中心 体温感应器的玩家。这些热受体在寒冷敏感的神经元/细胞中表达 外围设备。过去二十年的研究发现，大量的色氨酸家族通道是热的 感受器能够感知从33摄氏度到53摄氏度以上的全方位温暖和高温。 对动物如何感知热量有了相当清楚的了解。相比之下，人们对冷感知之甚少。 到目前为止，只有一个寒冷受体(TRPM8)被鉴定出来。TRPM8通过一种 激活阈值为~26°C，并调节凉爽感觉。因为动物和人类显然有能力 感官温度低于26摄氏度，TRPM8基因敲除小鼠对有毒寒冷表现出强大的反应， 未知的寒冷受体，特别是那些感知有害寒冷的受体，肯定存在，但仍有待识别。这个 线虫是一种广泛应用于感觉生物学研究的遗传模式生物。与哺乳动物一样，C. 优雅的人能感觉到全方位的温度信号。重要的是，感官受体和通道倾向于 在进化上保守的线虫。这一点，加上它的生成时间短(~3天)和方便 丰富的遗传工具，使线虫成为识别新的寒冷受体的理想系统。因此，我们 设计并实施了一项针对线虫冷感突变体的无偏见、基于活动的遗传筛查， 使用实时聚合酶链式反应热循环仪。我们鉴定了GLR-3，一种海藻酸型谷氨酸受体同系物，是一种 一种新型的冷感受器，在线虫中介导冷感。令人惊讶的是，GLR-3同源物GluK2 在异源系统中，小鼠和人类都可以作为寒冷的感受器。我们还发现， 小鼠GluK2表达于外周背根神经节感觉神经元。GluK2的激活阈值低于 20摄氏度，这表明它主要感觉有害的寒冷，而不是凉爽的温度。因为谷氨酸受体 众所周知，这些结果是通过中枢神经系统中的突触传递化学信号的 令人惊讶的是，中枢化学感受器在外围发挥热感受器的作用，这是一个引人注目的例子。 尽管有这些令人振奋的观察结果，但仍有许多问题没有得到回答，特别是关于 冷感觉中的哺乳动物GluK2。例如，GluK2是否调节小鼠的冷感？如果是这样的话，是如何做到的呢？ 在这里，我们建议通过检验几个假设来解决这些问题。为此，我们将利用 来自两个研究小组的专业知识，使用结合分子遗传学的多学科方法， 行为分析、钙质成像和电生理学。拟议的研究不仅将提供新颖的 对冷感机制的洞察，也揭示了谷氨酸受体在 外围。 。

The ability to sense environmental temperature is essential for life. Molecular thermal sensors are a central player in thermosensation. These thermal receptors are expressed in cold-sensitive neurons/cells in the periphery. Work in the past two decades has identified a large number of TRP family channels as heat receptors that sense a full range of warm and hot temperatures, spanning from 33°C to over 53°C. This has led to a fairly clear understanding of how animals sense heat. By contrast, little is known about cold sensation. Thus far, only one cold receptor (TRPM8) has been identified. TRPM8 senses cool temperatures with an activation threshold at ~26°C and mediates cool sensation. As animals and humans are clearly capable of sensing temperatures below 26°C, and TRPM8 knockout mice show robust responses to noxious cold, unknown cold receptors, particularly those sensing noxious cold, must exist but remain to be identified. The nematode C. elegans is a popular genetic model organism for sensory biology research. Like mammals, C. elegans senses a full range of temperature cues. Importantly, sensory receptors and channels tend to be evolutionarily conserved in C. elegans. This, together with its short generation time (~3 days) and facile and rich genetic tools, makes C. elegans an ideal system for identifying novel cold receptors. We therefore designed and conducted an unbiased, activity-based genetic screen for cold-sensing mutants in C. elegans, using a real-time PCR thermocycler. We identified GLR-3, a kainate-type glutamate receptor homolog, as a novel type of cold receptor that mediates cold sensation in C. elegans. Strikingly, the GLR-3 homolog GluK2 from fish, mouse and human can all function as a cold receptor in heterologous systems. We also found that mouse GluK2 is expressed in the peripheral DRG sensory neurons. The activation threshold of GluK2 is below 20°C, suggesting that it mainly senses noxious cold rather than cool temperatures. As glutamate receptors are best known to transmit chemical signals across synapses in the central nervous system, these results present a striking case where a central chemical receptor, surprisingly, functions as a thermal receptor in the periphery. Despite these exciting observations, many unanswered questions remain, particularly regarding the role of mammalian GluK2 in cold sensation. For example, does GluK2 mediate cold sensation in mice? If so, how? Here, we propose to address these questions by testing several hypotheses. To do so, we will leverage the expertise from two research groups using a multidisciplinary approach combining molecular genetics, behavioral analysis, calcium imaging, and electrophysiology. The proposed research will not only provide novel insights into the mechanisms of cold sensation, but also unveil an unexpected role of glutamate receptors in the periphery. .