Carotid Body Chemoreception: Mechanism & Development

颈动脉体化学感受：机制

• 批准号: 6744725
• 负责人: DAVID F. DONNELLY
• 金额: $ 32.7万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-05 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6744725
• 关键词: action potentials; biological signal transduction; carotid body; developmental neurobiology; hypoxia; ion channel blocker; laboratory mouse; laboratory rat; nerve endings; plethysmography; protein isoforms; single cell analysis; sodium channel; soma; tissue /cell culture

DESCRIPTION (provided by applicant): The primary hypoxia sensor of the cardio-respiratory system is the carotid body, which is relatively insensitive at birth and matures over the first 1-2 weeks of life. Although the mechanism of chemotransduction remains obscure, glomus cells, secretory cells apposed to the afferent nerve endings, as well as the nerve endings themselves appear to form the critical chemoreceptive unit. Current models propose that hypoxia causes release of an excitatory transmitter, but identification of the purported excitatory transmitter has proven elusive and our previous results, as well those of other laboratories, demonstrate a dissociation between glomus cell secretion and afferent nerve activity. The proposed work outlines two steps in understanding the mechanism of transduction: firstly, to understand the mechanism of spike generation and secondly, to understand how the generation process is controlled by hypoxia. Towards the first aim, we demonstrate: i) that the spike generation process is highly sensitive to external Na+ perturbation or drugs which target Na+ channels, ii) chemoreceptor afferent neurons express a limited and consistent Na+ channel profile and iii) isolated, chemoreceptor afferent neurons are able to generate spontaneous action potentials which resemble the pattern as generated by the afferent nerve ending. Based on the preliminary results, our general hypothesis is that the nerve terminals are the site of action potential generation through an endogenous process, specifically, a persistent Na+ current. The proposed work: 1) uses RT-PCR and immunocytochemistry to identify Na+ channel isoforms at the soma and nerve terminals of chemoreceptor neurons; 2) examines the consequences of Na+ current perturbations on the respiratory response to hypoxia and chemoreceptor activity following drugs which target fast Na+ currents or loss (knockout) of isoforms Navl.6 and Navl.8; 3) examines the effects of disruption of Na+ channel underexpression/overexpression on the ability of the soma to generate spontaneous action potentials. The anticipated results will provide acceptance or rejection of this unique model of chemoreceptor transduction. If supported, the model should lead to a pharmacologic targeting of these processes for the improved treatment of apnea and/or dyspnea.

描述(申请人提供)：心肺系统的主要缺氧感应器是颈动脉小体，出生时相对不敏感，在出生后1-2周内成熟。尽管化学转导的机制尚不清楚，但球状细胞、与传入神经末梢相对的分泌细胞以及神经末梢本身似乎构成了关键的化学感受单位。目前的模型认为，缺氧导致兴奋性递质的释放，但对所谓的兴奋性递质的识别已被证明是难以捉摸的，我们之前的结果以及其他实验室的结果表明，球体细胞分泌和传入神经活动之间存在分离。这项工作概述了理解信号转导机制的两个步骤：第一，了解脉冲产生的机制；第二，了解缺氧是如何控制产生过程的。对于第一个目标，我们证明：i)棘波的产生过程对外界的Na+扰动或针对Na+通道的药物高度敏感，ii)化学感受器传入神经元表达有限而一致的Na+通道轮廓，iii)分离的化学感受性传入神经元能够产生类似于传入神经末梢所产生的自发动作电位。根据初步结果，我们的一般假设是神经末梢是通过内源性过程产生动作电位的部位，特别是持续的Na+电流。拟开展的工作包括：1)使用RT-PCR和免疫细胞化学方法鉴定化学感受器神经元胞体和神经末梢上的Na+通道异构体；2)检测针对快Na+电流的药物后Na+电流扰动对呼吸反应和化学感受器活性的影响；3)检测Na+通道低表达/高表达对胞体产生自发动作电位能力的影响。预期的结果将决定对这种独特的化学感受器转导模式的接受或拒绝。如果得到支持，该模型应该导致这些过程的药理学靶向，以改善呼吸暂停和/或呼吸困难的治疗。