Contribution of ASIC channels to intrinsic chemosensitivity of NTS neurons

ASIC 通道对 NTS 神经元内在化学敏感性的贡献

• 批准号: 8444755
• 负责人: Rafiq Huda
• 金额: $ 1.85万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444755
• 关键词: ASIC channel; Amiloride; Area; Biological Process; Blood - brain barrier anatomy; Brain; Brain Stem; Breathing; Carbon Dioxide; Cell Nucleus; Cells; Characteristics; Chemoreceptors; Chronic; Complement; Dendrites; Detection; Disease; Dorsal; Dyes; Electrophysiology (science); Environment; Exhibits; Functional disorder; Histological Techniques; Homeostasis; Hypercapnic respiratory failure; Imaging Device; In Vitro; Intervention; Ion Channel; Knowledge; Label; Laboratories; Location; Mediating; Membrane; Molecular; Molecular Biology; Morbidity - disease rate; Neurons; Nucleus solitarius; Partial Pressure; Pattern; Permeability; Physiological; Polymerase Chain Reaction; Process; Property; Proxy; Public Health; Respiration; Respiration Disorders; Reverse Transcription; Role; Sampling; Signal Transduction; Solutions; Stimulus; Structure of area postrema; Sudden infant death syndrome; Surface; Synapses; Syndrome; Techniques; Testing; Tracer; congenital central hypoventilation syndrome; desensitization; extracellular; gene therapy; in vivo; neurophysiology; novel; research study; respiratory; response; tool; voltage; ASIC channel; Amiloride; Area; Biological Process; Blood - brain barrier anatomy; Brain; Brain Stem; Breathing; Carbon Dioxide; Cell Nucleus; Cells; Characteristics; Chemoreceptors; Chronic; Complement; Dendrites; Detection; Disease; Dorsal; Dyes; Electrophysiology (science); Environment; Exhibits; Functional disorder; Histological Techniques; Homeostasis; Hypercapnic respiratory failure; Imaging Device; In Vitro; Intervention; Ion Channel; Knowledge; Label; Laboratories; Location; Mediating; Membrane; Molecular; Molecular Biology; Morbidity - disease rate; Neurons; Nucleus solitarius; Partial Pressure; Pattern; Permeability; Physiological; Polymerase Chain Reaction; Process; Property; Proxy; Public Health; Respiration; Respiration Disorders; Reverse Transcription; Role; Sampling; Signal Transduction; Solutions; Stimulus; Structure of area postrema; Sudden infant death syndrome; Surface; Synapses; Syndrome; Techniques; Testing; Tracer; congenital central hypoventilation syndrome; desensitization; extracellular; gene therapy; in vivo; neurophysiology; novel; research study; respiratory; response; tool; voltage

DESCRIPTION (provided by applicant): Breathing serves an indispensable biological function and determines essential physiological parameters such as pH and partial pressure of carbon dioxide (PCO2). Central chemosensory neurons detect changes in brain pH as a proxy for changes in PCO2 and cause compensatory changes in respiration to maintain homeostasis of these parameters. Dysfunction of these neurons results in severe morbidity and is implicated in disorders such as congenital central hypoventilation syndrome and sudden infant death syndrome. Yet, the exact molecular mechanisms underlying chemosensitivity have remained largely elusive. In particular, the identity of ion channels that mediate central chemoreception is currently unknown. My preliminary results suggest that the acid-sensing ion channel (ASIC) acts as a chemoreceptor in a subset of neurons located in the nucleus tractus solitarus (NTS), a brainstem region known to be chemosensitive in vivo. However, this raises an important concern: how can ASIC channels contribute to central chemoreception if they are widely expressed even in brain areas not implicated in this process. I hypothesize that a unique combination of ASIC channel properties that confer the requisite pH sensitivity and specific anatomical characteristics (such as dendritic orientation, and axonal projections) may allow a subpopulation of NTS neurons to functionally contribute to central chemoreception. Aim 1: Which features of ASIC channels confer chemosensitivity onto a subpopulation of NTS neurons? Biophysical, pharmacological, and molecular tools will be used to determine differences between properties of ASIC channels expressed in NTS neurons that respond to pH 7.0 (responders) and those that do not (non-responders). This will help establish how differences in these properties confer chemosensitivity to only a subset of NTS neurons. Aim 2: Do chemosensitive NTS neurons display unique anatomical properties befitting their function? These experiments will combine electrophysiology with anatomical and imaging tools to uncover the anatomical properties of NTS neurons that are chemosensitive in-vitro. Mere expression of pH sensitive channels cannot contribute to central chemoreception. Therefore, whether chemosensitive neurons have unique dendritic properties that would allow them to sample brain pH and the correct axonal projection pattern to provide synaptic drive to respiratory rhythm generating neurons will be determined.

描述（由申请人提供）：呼吸具有必不可少的生物学功能，并确定基本的生理参数，例如pH和二氧化碳的部分压（PCO2）。中央化学感应神经元检测到脑pH的变化是PCO2变化的代理，并导致呼吸变化以维持这些参数的稳态。这些神经元的功能障碍会导致严重的发病率，并与诸如先天中央中央低衰减综合征和猝死综合征等疾病有关。然而，化学敏感性基本的确切分子机制在很大程度上仍然难以捉摸。特别是，介导中央化学感受的离子通道的身份是 目前未知。我的初步结果表明，酸性离子通道（ASIC）在位于Tractus solitarus（NTS）的神经元子集中充当化学感受器，该神经元（NTS）是脑干区域，这是一个已知的体内化学敏感性的脑干区域。但是，这引起了一个重要的问题：如果ASIC渠道即使在不涉及此过程的大脑区域中得到广泛表达，ASIC渠道也会有助于中央化学感受。我假设赋予必要的pH敏感性和特定的解剖特征（例如树突状取向和轴突投射）的独特组合可以使NTS神经元的亚群在功能上有助于中央化学感受。 AIM 1：ASIC通道的哪些特征将化学敏感性赋予NTS神经元的亚群？生物物理，药理学和分子工具将用于确定在NTS神经元中对pH 7.0（响应者）响应的NTS神经元中表达的ASIC通道的差异和不反应者（非响应者）的差异。这将有助于确定这些性质的差异如何仅赋予NTS神经元子集的化学敏感性。 AIM 2：化学敏感的NTS神经元是否显示出适合其功能的独特解剖学特性？这些实验将将电生理学与解剖学和成像工具相结合，以揭示具有化学敏感性体外的NTS神经元的解剖学特性。仅pH敏感通道的表达不能导致中央化学感受。因此，将确定化学敏感性神经元具有独特的树突特性，可以确定将它们采样脑pH和正确的轴突投影模式，从而确定向呼吸节奏产生神经元的突触驱动。