Molecular Basis of Sensory Transduction in C. elegans

最柔和的微风、最粗糙的砂纸和最锋利的大头针都能被我们的身体感觉到 该系统由嵌入在皮肤中的数千个触敏机械感受器神经元组成。它 人们普遍认为，物理力是通过激活特殊的离子而转化为神经信号的 通道(称为机械-电转导或MET通道)，但对分子和 这一进程的物质基础仍然是初步的。所有的动物都有感觉触觉和最近的工作的能力 已经表明线虫和哺乳动物的体感神经元具有相似的反应动力学(综述 收录于Geffeney and Goodman，Neuron 74：609,2012)。这种功能守恒在依赖于 DEG/ENaC或Trp通道蛋白形成MET通道，这一发现表明该反应 特性主要是由细胞环境决定的，而不是离子通道蛋白固有的。这个 拟议研究计划的长期目标是了解细胞膜和细胞骨架是如何 调节触摸感受器神经元(TRN)中表达的MET通道的物理力量的传递 发现与触摸诱发的MET通道门控相关的结构重排。这位将军 方法是将已识别的TRNS中MET通道门控的活体记录与遗传学相结合 线虫中的扰动1)改变多不饱和脂肪酸和细胞的生物合成 膜功能，2)破坏微管和血影蛋白细胞骨架，3)破坏所选择的结构域 MEC-4蛋白对钠选择性天然MET通道的形成至关重要。这项工作将是 与光遗传学研究相结合，旨在确定影响MET通道但不影响下游的因素 信号事件和异源细胞中表达的MET通道的生物物理分析。这个 拟议的研究结合了感觉生物物理学、活体电记录方面的专业知识 通过对线虫神经元的鉴定、遗传分析，得出对线虫的深刻认识 触碰。从这些研究中学到的东西有可能提高对触摸感觉和 在疾病、化疗期间和正常衰老的结果中，它的功能障碍。

The gentlest breeze, the roughest sandpaper, and the sharpest pin are detected by our somatosensory system, which is composed of thousands of touch-sensitive mechanoreceptor neurons embedded in the skin. It is widely understood that physical force is transduced into neural signals through activation of specialized ion channels (called 'mechano-electrical transduction' or MeT channels), but understanding of the molecular and physical basis of this process remains rudimentary. All animals have the ability to sense touch and recent work has shown that nematode and mammalian somatosensory neurons have similar response dynamics (reviewed in Geffeney and Goodman, Neuron 74:609, 2012). This functional conservation is seen in neurons that rely on either DEG/ENaC or TRP channel proteins to form MeT channels, a finding which implies that response properties are conferred primarily by the cellular environment and not intrinsic to the ion channel proteins. The long-term goal of the proposed research program is to understand how the cell membrane and cytoskeleton regulate the delivery of physical force to MeT channels expressed in touch receptor neurons (TRNs) and discover the structural rearrangements associated with touch-evoked MeT channel gating. The general approach will be to combine in vivo recording of MeT channel gating in identified TRNs with genetic perturbations in C. elegans nematodes that 1) alter biosynthesis of polyunsaturated fatty acids and cell membrane function, 2) disrupt the microtubule and spectrin cytoskeleton and 3) disrupt selected domains in the MEC-4 proteins crucial to the formation of the sodium-selective native MeT channels,. This work will be paired with optogenetics studies designed to identify factors that affect MeT channels, but not downstream signaling events and with biophysical analysis of MeT channels expressed in heterologous cells. The proposed research combines expertise in sensory biophysics, in vivo electrical recording from identified C. elegans neurons, genetic analysis, to derive a profound understanding of the sense of touch. What is learned from these studies has the potential to improve understanding of touch sensation and its dysfunction in disease, during chemotherapy and as a consequence of normal aging.