CAROTID BODY EXCITATION--NEW CONCEPT

颈动脉体兴奋--新概念

• 批准号: 6537492
• 负责人: MACHIKO SHIRAHATA
• 金额: $ 24.85万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-05 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537492
• 关键词: calcium channel; calcium flux; carotid body; cats; cellular polarity; chemoreceptors; hypoxia; immunocytochemistry; neurotransmitter transport; nicotinic receptors; oxygen; potassium channel; receptor sensitivity; tissue /cell culture; voltage /patch clamp; voltage gated channel

DESCRIPTION (Applicant's abstract): The carotid body is a major chemoreceptor organ whose excitation causes reflex responses in cardiopulmonary, renal and endocrine systems. Although the mechanisms of carotid body excitation are not yet clear, essential steps include the depolarization of chemosensitive glomus cells, the increase in glomus cell intracellular calcium and the release of neurotransmitters. Many studies point to the involvement of oxygen-sensitive potassium channels, but a causal relationship between the inhibition of these channels and the depolarization of glomus cells during hypoxia has not yet been established. Since cat glomus cells release acetylcholine even under normoxic/normocapnic conditions, we hypothesize that hypoxia augments the activity of neuronal nicotinic acetylcholine receptors and/or enhances the sensitivity of acetylcholine receptors for acetylcholine. This initiates the depolarization of glomus cells and the increase in intracellular calcium. Oxygen-sensitive potassium channels and voltage-gated calcium channels participate in the later phase of the changes. Preliminary data have shown that: 1) cat glomus cells expressed alpha-4 subunit containing nicotinic acetylcholine receptors, 2) acetylcholine-induced inward current and carotid body neural output were enhanced by a mild decrease in oxygen tension from normoxic levels, 3) acetylcholine increased calcium of carotid body cells, 4) oxygen-sensitive potassium current was linearly inhibited by decreasing oxygen, and 5) increased carotid body neural output in hypoxia was inhibited by L-type voltage gated calcium channels. Specific aims are to investigate: 1) the role of acetylcholine and nicotinic acetylcholine receptors for initiating the depolarization of glomus cells and the increase in calcium, 2) the contribution of oxygen sensitive potassium channels in the late phase of glomus cell depolarization during hypoxia, 3) the contribution of voltage gated calcium channels to the late phase of the calcium increase in glomus cells during hypoxia. Patch clamp, microfluorometric, and immunocytochemical techniques are to be used. This innovative proposal will advance the understanding of the excitation mechanisms of glomus cells. Once the chemotransductive mechanisms are understood, pharmacological or genetic tools can be developed to alter the carotid body function to levels desirable for treating carotid body related pathological conditions such as sudden infant death syndrome and hemodynamic changes in sleep apnea patients.

描述（申请人摘要）：颈动脉体是主要的化学感受器 兴奋引起心肺、肾和 内分泌系统虽然颈动脉体兴奋的机制不是 然而，明确的，必要的步骤包括去极化的化学敏感性球 细胞，血管球细胞内钙的增加和释放 神经传递素许多研究指出， 钾通道，但这些抑制之间的因果关系 通道和缺氧时血管球细胞的去极化尚未被证实。 确立了习因为猫的血管球细胞即使在 在常氧/常碳酸条件下，我们假设缺氧增加了 神经元烟碱乙酰胆碱受体的活性和/或增强 乙酰胆碱受体对乙酰胆碱的敏感性。这将启动 血管球细胞的去极化和细胞内钙的增加。 氧敏感性钾通道和电压门控性钙通道 参与后期的变革。初步数据显示 结果表明：1）猫血管球细胞表达含有烟碱的α 4亚基， 乙酰胆碱受体，2）乙酰胆碱诱导的内向电流和颈动脉 机体神经输出通过氧张力的轻度降低而增强， 常氧水平，3）乙酰胆碱增加颈动脉体细胞的钙，4） 氧敏感性钾电流随氧浓度降低而线性抑制， 缺氧时颈动脉体神经输出的增加被L-型 电压门控钙通道。具体目标是调查：1）作用 乙酰胆碱和烟碱型乙酰胆碱受体， 血管球细胞的去极化和钙的增加，2）的贡献 氧敏感性钾通道在血管球细胞晚期的作用 3）电压门控性钙通道的作用 通道的晚期阶段的钙增加，在球细胞， 缺氧膜片钳，显微荧光，免疫细胞化学技术， 以供使用。这一创新的建议将促进对 血管球细胞的兴奋机制。一旦化学传导机制 可以理解的是，可以开发药理学或遗传学工具来改变 颈动脉体功能达到治疗颈动脉体相关疾病所需的水平 病理条件，如婴儿猝死综合征和血流动力学 睡眠呼吸暂停综合征的症状

项目成果

Genetic influence on carotid body structure in DBA/2J and A/J strains of mice.

DBA/2J 和 A/J 品系小鼠颈动脉体结构的遗传影响。

• DOI: 10.1007/0-387-31311-7_16
• 发表时间: 2006
• 期刊: Advances in experimental medicine and biology
• 作者: Yamaguchi,Shigeki;Balbir,Alexander;Okumura,Mariko;Schofield,Brian;Coram,Judith;Tankersley,ClarkeG;Fitzgerald,RobertS;O'Donnell,ChristopherP;Shirahata,Machiko
• 通讯作者: Shirahata,Machiko

Hypoxic augmentation of neuronal nicotinic acetylcholine receptors and carotid body function.

缺氧增强神经元烟碱乙酰胆碱受体和颈动脉体功能。

• DOI: 10.1007/978-1-4419-9280-2_35
• 发表时间: 2003
• 期刊: Advances in experimental medicine and biology
• 作者: Shirahata,Machiko;Higashi,Tomoko;Mendoza,JeffreyA;Hirasawa,Serabi
• 通讯作者: Hirasawa,Serabi

ACh differentially modulates voltage-gated K channels in glomus cells between DBA/2J and A/J strains of mice.

ACh 差异调节 DBA/2J 和 A/J 品系小鼠的血管球细胞中的电压门控 K 通道。

• DOI: 10.1007/978-1-4419-9280-2_34
• 发表时间: 2003
• 期刊: Advances in experimental medicine and biology
• 作者: Yamaguchi,Shigeki;Higashi,Tomoko;Hori,Yuichi;Shirahata,Machiko
• 通讯作者: Shirahata,Machiko

Differential expression of oxygen sensitivity in voltage-dependent K channels in inbred strains of mice.

近交系小鼠电压依赖性 K 通道氧敏感性的差异表达。

• DOI: 10.1007/0-387-31311-7_32
• 发表时间: 2006
• 期刊: Advances in experimental medicine and biology
• 作者: Otsubo,Toshiki;Yamaguchi,Shigeki;Okumura,Mariko;Shirahata,Machiko
• 通讯作者: Shirahata,Machiko

Hypoxic modulation of the cholinergic system in the cat carotid glomus cell.

猫颈动脉球细胞中胆碱能系统的缺氧调节。

• DOI: 10.1007/0-387-31311-7_43
• 发表时间: 2006
• 期刊: Advances in experimental medicine and biology
• 作者: Mendoza,JeffreyA;Chang,Irene;Shirahata,Machiko
• 通讯作者: Shirahata,Machiko