Mechanism of oxygen sensing by chemoreceptor cells

化学感受器细胞氧传感机制

基本信息

批准号：
8522223
负责人：
Donghee Kim
金额：
$ 33.09万
依托单位：
ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-03 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8522223
关键词：
Action Potentials Acute Address Asthma Back Binding Biological Process Blood Bradycardia Brain Stem Breathing Bronchopulmonary Dysplasia Carbon Monoxide Cardiovascular Diseases Cardiovascular system Carotid Arteries Carotid Body Cell Hypoxia Cells Chemoreceptors Cystathionine Data Environmental air flow Enzymes Feedback Functional disorder Generations Glomus Cell Goals Heart failure Hydrogen Sulfide Hypertension Hypoxia Ion Channel Knockout Mice Knowledge Lung Lyase Mediating Membrane Modeling Monovalent Cations Mus Nerve Nerve Endings Outcome Oxygen Oxygen measurement, partial pressure, arterial Peripheral Physiological Potassium Channel Process Property Rattus Research Respiration Disorders Respiratory Center Role Scheme Signal Transduction System TRPM5 gene Testing Tissues afferent nerve autonomic nerve base carotid sinus feeding improved inhibitor/antagonist receptor research study respiratory response tool voltage

项目摘要

DESCRIPTION (provided by applicant): Chemoreceptor cells in the carotid body (CB cells), in response to hypoxia, initiate homeostatic mechanisms to regulate breathing and autonomic nerve system activity. A widely accepted model for O2 sensing by CB cells is that hypoxia inhibits K+ current and thereby causes depolarization, opening of voltage-dependent Ca2+ channels, and elevation of [Ca2+]i. Upon rise of [Ca2+]i, CB cells secrete transmitters that act on sensory nerve terminals to elicit action potentials that reach the brainstem cardio-respiratory centers. In CB cells, hypoxia is believed to target a number of K+ channels to cause excitation. One of the K+ channels inhibited by hypoxia is TASK (TASK-1 and TASK-3) that is highly expressed in CB cells and active across the physiological range of Em. The mechanism of inhibition of TASK by hypoxia is not yet known. Recently, we discovered a Na+ permeable channel that is activated by hypoxia (hypoxia-activated or HA channel) in rat CB cells. Therefore, we hypothesize that inhibition of K+ current and activation of Na+ current both contribute to hypoxia-induced depolarization of CB cells. Recent studies suggest that hydrogen sulfide (H2S) is generated during hypoxia and mediates the hypoxia-induced increase in carotid sinus nerve activity and ventilation. However, the role of H2S in hypoxia-induced excitation of CB cells remains undefined. Therefore, we propose three specific aims to identify the mechanisms of hypoxia-induced modulation of TASK and the HA channel, and the role of the HA channel in hypoxia-induced excitation in CB cells. Aim 1 tests the hypothesis that hypoxia inhibits TASK via generation of H2S, and investigates the mechanism of this inhibition. The role of hemeoxygenase-2 in this process is also studied, as carbon monoxide regulates the activity of cystathionine-?-lyase that generates H2S. Preliminary data show that the HA channel is a Ca2+-activated monovalent cation channel. Aim 2 therefore tests the hypothesis that the HA channel is a Ca2+-sensitive TRP ion channel, and that H2S serves as a signal in hypoxia-induced activation of the HA channel. Aim 3 tests the role of the HA channel as part of a positive feedback mechanism involved in the excitation of CB cells during moderate to severe hypoxia. The role of the HA channel in the activation of BK, as part of the negative feed-back mechanism to limit over- excitation is also tested. The contribution of the HA channel to CB cell excitation s studied using an inhibitor of the HA channel and mice lacking the TRP ion channel. The outcome of these experiments should establish the HA channel as a new target of hypoxia, and also help to define the role of H2S as a hypoxia-generated signal that modulates both TASK and the HA channel. These studies should fill an important knowledge gap in our understanding of the O2 sensing mechanisms by carotid body chemoreceptors.

描述（由申请人提供）：颈动脉体中的化学感受器细胞（CB细胞）响应缺氧，启动稳态机制来调节呼吸和自主神经系统活动。 CB 细胞广泛接受的 O2 传感模型是缺氧抑制 K+ 电流，从而导致去极化、电压依赖性 Ca2+ 通道开放和 [Ca2+]i 升高。 [Ca2+]i 升高后，CB 细胞分泌递质，作用于感觉神经末梢引发动作电位，到达脑干心肺中枢。在 CB 细胞中，缺氧被认为会针对多个 K+ 通道引起兴奋。 TASK（TASK-1 和 TASK-3）是缺氧抑制的 K+ 通道之一，它在 CB 细胞中高表达，并在 Em 的生理范围内活跃。缺氧抑制TASK的机制尚不清楚。最近，我们在大鼠CB细胞中发现了缺氧激活的Na+通透性通道（缺氧激活或HA通道）。因此，我们假设 K+ 电流的抑制和 Na+ 电流的激活都有助于缺氧诱导的 CB 细胞去极化。最近的研究表明，硫化氢 (H2S) 在缺氧过程中产生，并介导缺氧引起的颈动脉窦神经活动和通气的增加。然而，H2S 在缺氧诱导的 CB 细胞兴奋中的作用仍不清楚。因此，我们提出了三个具体目标，以确定缺氧诱导的 TASK 和 HA 通道调节机制，以及 HA 通道在缺氧诱导的 CB 细胞兴奋中的作用。目标 1 检验缺氧通过生成 H2S 抑制 TASK 的假设，并研究这种抑制的机制。还研究了 hemeoxygenase-2 在此过程中的作用，因为一氧化碳调节产生 H2S 的胱硫醚-β-裂解酶的活性。初步数据表明HA通道是Ca2+激活的单价阳离子通道。因此，目标 2 检验了以下假设：HA 通道是 Ca2+ 敏感的 TRP 离子通道，并且 H2S 在缺氧诱导的 HA 通道激活中充当信号。目标 3 测试 HA 通道作为正反馈机制的一部分的作用，该机制参与中度至重度缺氧期间 CB 细胞的兴奋。还测试了 HA 通道在 BK 激活中的作用，作为限制过度兴奋的负反馈机制的一部分。使用HA通道抑制剂和缺乏TRP离子通道的小鼠研究了HA通道对CB细胞兴奋的贡献。这些实验的结果应该将 HA 通道确立为缺氧的新目标，并且还有助于定义 H2S 作为缺氧产生的信号来调节 TASK 和 HA 通道的作用。这些研究应该填补我们对颈动脉体化学感受器 O2 传感机制的理解的重要知识空白。