Molecular Basis of Sensory Transduction in C. elegans

最轻柔的微风、最粗糙的砂纸和最锋利的大头针都能被我们的体感感知到 系统，它是由成千上万的触摸敏感的机械神经元嵌入皮肤。它 物理力通过激活特定的离子被转换成神经信号 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很薄弱。所有动物都有感知触觉和最近工作的能力 已经表明线虫和哺乳动物的躯体感觉神经元具有相似的反应动力学（综述 在Geffeney和Goodman，Neuron 74：609，2012中）。这种功能保守性在依赖于 DEG/ENaC或TRP通道蛋白形成MeT通道，这一发现表明， 这些特性主要由细胞环境赋予，而不是离子通道蛋白质固有的。的 拟议的研究计划的长期目标是了解细胞膜和细胞骨架如何 调节物理力向触觉受体神经元（TRN）中表达的MeT通道的传递， 发现与触摸诱发的MeT通道门控相关的结构重排。总 一种方法是将联合收割机在体内记录鉴定的TRN中的MeT通道门控与遗传学结合起来， 扰动C。1）改变多不饱和脂肪酸和细胞生物合成 膜功能，2）破坏微管和血影蛋白细胞骨架，3）破坏细胞膜中的选定结构域， 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 与旨在确定影响MeT通道但不影响下游的因素的光遗传学研究配对， 信号传导事件和异源细胞中表达的MeT通道的生物物理分析。的 拟议的研究结合了感觉生物物理学的专业知识， 识别C。线虫神经元的遗传分析，得出深刻的认识， touch.从这些研究中学到的东西有可能提高对触觉的理解， 它在疾病中、化疗期间以及作为正常衰老的结果而功能障碍。

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.