Cellular and Ion Channel Mechanisms Underlying the Sense of Light Touch in Mammals

摘要： 触觉对于日常任务至关重要，包括触觉辨别，社会互动， 环境探索该项目的总体目标是识别细胞和分子 哺乳动物触觉的潜在机制。以前的研究表明，默克尔光盘，一个 主要类型的触觉终末器官，在触觉中起中心作用。默克尔光盘位于触摸 全身的敏感点，特别是在人类的指尖和胡须毛囊的非灵长类动物 哺乳动物默克尔盘由一个默克尔细胞和一个Aβ传入末梢（默克尔末梢）组成， 突触样结构。我们和其他人以前已经表明，默克尔细胞上的Piezo 2通道是 触摸传感器。我们进一步表明，触觉刺激激活默克尔细胞中的Piezo 2通道， Ca 2 +-动作电位，其导致Aβ-传入冲动和行为触觉反应。但 默克尔细胞上的突触诱导的兴奋性信号传递到默克尔末梢的机制 仍然难以捉摸，是这次更新申请的重点。我们的中心假设是酸敏感离子 通道（ASICs）是兴奋性突触后受体，质子是介导兴奋性突触后受体的主要递质。 兴奋性突触后电流（EPSC）和默克尔盘的突触传递。我们将测试这本小说 假设有以下具体目标。目标1。描述默克尔EPSC的基本性质 Aβ传入纤维的末梢。目标2.证明EPSC由位于默克尔的ASIC介导 结局目标3。阐明质子激活ASIC是导致EPSC产生的原因， 默克尔的结局。目标4。鉴定在默克尔末端介导EPSC的功能性ASIC的同种型。 将在啮齿动物须毛的默克尔末端的半节点处应用压力膜片钳记录 记录机械刺激诱发的EPSC，以及其他技术，包括突触 生理学、药理学、免疫组织化学和小鼠遗传学将用于实现上述目标 目标。通过实现上述目标，我们将发现一个新的基本机制， 触觉信号在默克尔盘的突触传递。这将大大推进科学知识 关于触觉背后的分子机制。它还可能对以下方面产生重要影响： 机械感觉功能障碍（例如，触觉丧失）在临床条件下观察到， 糖尿病和化疗

ABSTRACT: The sense of touch is critical for daily tasks including tactile discrimination, social interaction, and environmental exploration. The overall objective of this project is to identify the cellular and molecular mechanisms underlying the sense of touch in mammals. Previous studies have shown that Merkel discs, a main type of tactile end organ, play a central role in the sense of touch. Merkel discs are located in touch sensitive spots throughout the body especially at human fingertips and whisker hair follicles of non-primate mammals. A Merkel disc consists of a Merkel cell and an Aβ-afferent ending (Merkel ending) to form a synapse-like structure. We and others have previous shown that the Piezo2 channel on Merkel cells is the sensor of touch. We have further shown that tactile stimuli activate Piezo2 channels in Merkel cells to result in Ca2+-action potentials, which leads to Aβ-afferent impulses and behavioral tactile responses. However, the mechanism by which tactile-induced excitatory signals on Merkel cells are transmitted to Merkel endings remains elusive and is the focus of this renewal application. Our central hypothesis is that acid sensing ion channels (ASICs) are the excitatory postsynaptic receptors and proton is the principal transmitter to mediate excitatory postsynaptic currents (EPSCs) and synaptic transmission at Merkel discs. We will test this novel hypothesis with the following specific aims. Aim 1. Characterize the fundamental nature of EPSCs at Merkel endings of Aβ-afferent fibers. Aim 2. Demonstrate that EPSCs are mediated by ASICs located at Merkel endings. Aim 3. Elucidate that activation of ASICs by protons is responsible for the generation of EPSCs at Merkel endings. Aim 4. Identify the isoform of functional ASICs that mediate EPSCs at Merkel endings. Pressure-patch-clamp recordings will be applied at the heminode of Merkel endings in rodent whisker hair follicles to record EPSCs that are evoked by mechanical stimulation, and other techniques including synaptic physiology, pharmacology, immunohistochemistry, and mouse genetics will be used to achieve the above aims. By completing the above aims, we will have uncovered a new fundamental mechanism mediating synaptic transmission of tactile signals at Merkel discs. This will significantly advance scientific knowledge about molecular mechanisms underlying the sense of touch. It may also have important implications in mechanical sensory dysfunctions (e.g., loss of touch sensation) seen under clinical conditions such as diabetes and chemotherapy.