Mechanism of oxygen sensing by chemoreceptor cells

化学感受器细胞氧传感机制

• 批准号: 8881290
• 负责人: Donghee Kim
• 金额: $ 34.24万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-03 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8881290
• 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; biophysical properties; carotid sinus; feeding; improved; inhibitor/antagonist; receptor; research study; respiratory; response; tool; voltage

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-γ-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（由适用提供）：颈动脉体（CB细胞）中的化学感受器细胞，响应缺氧，启动稳态机制以调节呼吸和自主神经系统活动。 CB细胞对O2敏感性的广泛接受的模型是，缺氧抑制K+电流，从而导致去极化，打开电压依赖性Ca2+通道以及[Ca2+] i的升高。在[Ca2+] I的兴起时，CB细胞秘密发射器作用于 感官神经终端引起到达脑干心脏呼吸中心的动作电位。在CB细胞中，据信缺氧针对许多K+通道引起兴奋。缺氧抑制的K+通道之一是任务（Task-1和Task-3），它​​在CB细胞中高度表达并在EM的物理范围内活跃。缺氧对任务抑制的机制尚不清楚。最近，我们发现了一个Na+渗透通道，该通道在大鼠CB细胞中被低氧（缺氧或HA通道）激活。因此，我们假设抑制K+电流和Na+电流的激活都导致缺氧诱导的CB细胞去极化。最近的研究表明，硫化氢（H2S）是在缺氧期间产生的，并介导缺氧引起的颈动脉神经活性和通风的增加。然而，H2在缺氧引起的CB细胞兴奋中的作用仍然不确定。因此，我们提出了三个特定的目的，以确定缺氧诱导的任务和HA通道的调节机制，以及HA通道在低氧诱导的CB细胞中的兴奋中的作用。 AIM 1检验以下假设：缺氧通过H2s的产生抑制任务，并研究了这种抑制作用的机制。还研究了Hemeoxyganase-2在此过程中的作用，因为一氧化碳调节了产生H2S的胱淀粉-γ-溶解酶的活性。初步数据表明，HA通道是Ca2+激活的单价阳离子通道。因此，AIM 2检验了HA通道是Ca2+敏感的TRP离子通道的假设，并且H2S在缺氧诱导的HA通道激活中充当信号。 AIM 3测试HA通道作为中等至重度缺氧期间CB细胞兴奋的正反馈机制的一部分。还测试了HA通道在BK激活中的作用，这是负饲料机制限制过度激发的一部分。使用HA通道的抑制剂和缺乏TRP离子通道的小鼠，HA通道对CB细胞兴奋S研究的贡献。这些实验的结果应建立HA通道为缺氧的新目标，并有助于将H2S的作用定义为调节任务和HA通道的缺氧生成的信号。这些研究应填补我们对颈动脉体化学感受器对O2敏感性机制的理解的重要知识差距。

项目成果

Role of K₂p channels in stimulus-secretion coupling.

K-p 通道在刺激-分泌耦合中的作用。

• DOI: 10.1007/s00424-014-1663-3
• 发表时间: 2015
• 期刊: Pflugers Archiv : European journal of physiology
• 作者: Kim,Donghee;Kang,Dawon
• 通讯作者: Kang,Dawon

THIK-1 (K2P13.1) is a small-conductance background K(+) channel in rat trigeminal ganglion neurons.

• DOI: 10.1007/s00424-013-1358-1
• 发表时间: 2014-07
• 期刊: PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
• 影响因子: 4.5
• 作者: Kang, Dawon;Hogan, James O.;Kim, Donghee
• 通讯作者: Kim, Donghee

Hydrogen sulfide and hypoxia-induced changes in TASK (K2P3/9) activity and intracellular Ca(2+) concentration in rat carotid body glomus cells.

• DOI: 10.1016/j.resp.2015.04.012
• 发表时间: 2015-08-15
• 期刊: Respiratory physiology & neurobiology
• 影响因子: 2.3
• 作者: Kim D;Kim I;Wang J;White C;Carroll JL
• 通讯作者: Carroll JL

Modulation of K2P3.1 (TASK-1), K2P9.1 (TASK-3), and TASK-1/3 heteromer by reactive oxygen species.

• DOI: 10.1007/s00424-012-1159-y
• 发表时间: 2012-11
• 期刊: PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
• 影响因子: 4.5
• 作者: Papreck, Justin R.;Martin, Elizabeth A.;Lazzarini, Ping;Kang, Dawon;Kim, Donghee
• 通讯作者: Kim, Donghee

Voltage- and receptor-mediated activation of a non-selective cation channel in rat carotid body glomus cells.

• DOI: 10.1016/j.resp.2016.12.005
• 发表时间: 2017-03
• 期刊: Respiratory physiology & neurobiology
• 影响因子: 2.3
• 作者: Wang J;Hogan JO;Kim D
• 通讯作者: Kim D