Modulation of Voltage-gated K Channels in Glomus Cells

血管球细胞中电压门控 K 通道的调节

• 批准号: 7089031
• 负责人: MACHIKO SHIRAHATA
• 金额: $ 23.95万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7089031
• 关键词: acetylcholine; calcium ion; carotid body; cats; charge coupled device camera; chemoreceptors; cholinergic receptors; gene expression; hypoxia; immunocytochemistry; ion channel blocker; laboratory mouse; oxygen tension; polymerase chain reaction; potassium channel; protein kinase C; tissue /cell culture; voltage /patch clamp; voltage gated channel

DESCRIPTION (provided by applicant): Systemic hypoxia is a potentially lethal situation for the animal. To protect major organs from irreversible damage, the carotid body, a primary arterial chemosensory organ, sends a message to the brain and induces various systemic responses. The mechanisms of hypoxic chemotransmission in the carotid body is not still clear, but the involvement of K+ channels and neurotransmitters has been indicated. Studies have shown that acetylcholine (ACh) plays an active role in the excitation of glomus cells. Accordingly, we hypothesized that interaction between ACh and voltage-gated K+ (Kv) channels plays an important role in the excitation of glomus cells. Our preliminary studies showed that low doses of ACh enhanced and high doses of ACh inhibited Kv current in cat glomus cells. We will extend these studies and investigate mechanisms involved in the modulation of Kv channels by ACh. Patch clamp, microfluorometric, gene expression array, RT-PCR and immunocytochemical techniques will be applied. Initially we will use our cat model, because we have already characterized Kv channels and cholinergic receptors in cat glomus cells. Contribution of nicotinic, muscarinic M1 and M2 receptors to the modulation of Kv current in relation to cytosolic Ca2+, PKC and tyrosine kinase will be investigated. These studies will reveal how the interaction between ACh and Kv channels occurs at subcellular level (Specific Aim 1). Subsequently, we will extend our studies to a mouse model (DBA/2J and A/J strains). Hypoxic ventilatory responses and glomus cell responses to ACh in these strains are substantially different. We have hypothesized that variations in cholinergic modulation of Kv channels are the bases of these differences (Specific aim 2). The studies in mice will show whether these differences are genetically controlled. The proposed studies will give new insight into mechanisms of the carotid body excitation. In the perspective of public health, understanding the chemosensory and chemotransductive mechanisms may be valuable for the treatment of some pathological conditions related to carotid body function such as primary hypertension, obstructive sleep apnea, abnormal ventilation in Prader-Willi syndrome, sudden infant death syndrome and congenital central hypoventilation syndrome. These diseases are known to have a genetic basis.

描述（由申请人提供）：全身缺氧对于动物来说是一种潜在的致命情况。为了保护主要器官免受不可逆的损害，颈动脉体（一种主要的动脉化学感应器官）向大脑发送信息并诱发各种全身反应。颈动脉体缺氧化学传递的机制尚不清楚，但已表明K+通道和神经递质的参与。研究表明乙酰胆碱（ACh）在血管球细胞的兴奋中发挥积极作用。因此，我们假设 ACh 和电压门控 K+ (Kv) 通道之间的相互作用在血管球细胞的兴奋中发挥重要作用。我们的初步研究表明，低剂量的ACh增强猫血管球细胞的Kv电流，高剂量的ACh抑制猫血管球细胞的Kv电流。我们将扩展这些研究并研究 ACh 调节 Kv 通道的机制。将应用膜片钳、微荧光、基因表达阵列、RT-PCR和免疫细胞化学技术。最初我们将使用我们的猫模型，因为我们已经表征了猫血管球细胞中的 Kv 通道和胆碱能受体。将研究烟碱、毒蕈碱 M1 和 M2 受体对与胞质 Ca2+、PKC 和酪氨酸激酶相关的 Kv 电流调节的贡献。这些研究将揭示 ACh 和 Kv 通道之间的相互作用如何在亚细胞水平发生（具体目标 1）。随后，我们将研究扩展到小鼠模型（DBA/2J 和 A/J 品系）。这些菌株的缺氧通气反应和血管球细胞对 ACh 的反应有很大不同。我们假设 Kv 通道的胆碱能调节的变化是这些差异的基础（具体目标 2）。对小鼠的研究将表明这些差异是否受到基因控制。拟议的研究将为颈动脉体兴奋机制提供新的见解。从公共卫生的角度来看，了解化学感应和化学传导机制可能对治疗一些与颈动脉体功能相关的病理状况具有重要意义，如原发性高血压、阻塞性睡眠呼吸暂停、普瑞德-威利综合征通气异常、婴儿猝死综合征和先天性中枢性低通气综合征等。已知这些疾病具有遗传基础。

项目成果

Benzodiazepines and GABA-GABAA receptor system in the cat carotid body.

• DOI: 10.1007/978-90-481-2259-2_19
• 发表时间: 2009
• 期刊: Advances in experimental medicine and biology
• 作者: Ayuko Igarashi;N. Zadzilka;M. Shirahata

Voltage-dependent K channels in mouse glomus cells are modulated by acetylcholine.

小鼠血管球细胞中的电压依赖性 K 通道受乙酰胆碱调节。

• DOI: 10.1007/0-387-31311-7_49
• 发表时间: 2006
• 期刊: Advances in experimental medicine and biology
• 作者: Otsubo,Toshiki;Yamaguchi,Shigeki;Shirahata,Machiko
• 通讯作者: Shirahata,Machiko

Differential Expression of Large-Conductance Ca-Activated K Channels in the Carotid Body between DBA/2J and A/J Strains of Mice.

• DOI: 10.3389/fncel.2011.00019
• 发表时间: 2011
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Otsubo T;Kostuk EW;Balbir A;Fujii K;Shirahata M
• 通讯作者: Shirahata M

Divergent postnatal development of the carotid body in DBA/2J and A/J strains of mice.

DBA/2J 和 A/J 品系小鼠颈动脉体的出生后发育存在差异。

• DOI: 10.1152/japplphysiol.01477.2010
• 发表时间: 2012
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: Kostuk,EricW;Balbir,Alexander;Fujii,Koichi;Fujioka,Akiko;Pichard,LuisE;Shirahata,Machiko
• 通讯作者: Shirahata,Machiko