KIR channel modulations in hypercapnic acidosis

高碳酸血症性酸中毒中的 KIR 通道调节

• 批准号: 6530690
• 负责人: CHUN JIANG
• 金额: $ 24.82万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6530690
• 关键词: G protein; Xenopus oocyte; brain stem; carbon dioxide tension; chemoreceptors; hypercapnia; laboratory rat; membrane potentials; microelectrodes; potassium channel; protein structure function; receptor coupling; respiratory acidosis; tissue /cell culture; voltage /patch clamp

DESCRIPTION (Applicant's abstract): As an early event in CO2 sensing, changes in membrane excitability have been demonstrated in brainstem CO2 chemo sensitive neurons, which seem to result from alternations in synaptic transmission, transporter activity and/or ion channel activation. Indeed, studies including ours have shown that K+ channels are the key players in controlling membrane excitability in these chemo sensitive neurons. We have found that the hypercapnia-induced depolarization is attenuated by antagonism of K+ channels, while blockade of synaptic transmission and several other ion channels has no effect. We have thereafter studied these CO2-sensitive K+ channels and demonstrated a novel CO2 sensing mechanism in these channels. This mechanism relies on the inherent pH-sensing and channel-gating processes of inward rectifier K+ channels, allowing the change in PCO2 levels to be coupled to a nonexpanding change in membrane excitability. Among these CO2-sensitive K+ channels, the heteromeric Kir4.1-Kir5.1 is particularly interesting. With a linear working range at physiologic pH levels, these channels can detect both hypercapnia and hypocapnia. These plus their brainstem-specific expression make them the highly promising candidates for the potential CO2 sensing molecules in the central CO2 chemoreceptors. Clearly, detailed studies of the molecular mechanisms underlying the CO2 sensing in these K+ channels may yield important information of CO2 chemoreception. Thus, we have proposed experiments to test three specific hypotheses: 1) the heteromeric Kir4.1 -Kir5.1 channels act as CO2 sensors 2) the Kir4.1 -Kir5.1 channels are specifically expressed in brainstem neurons; and 3) CO2 enhances membrane excitability of chemo sensitive neurons by inhibiting the Kir4.1 -Kir5.1 channels. The outcome of these studies will not only improve our understanding of CO2 chemo receptive physiology but also may help the design of medical interventions by manipulating these cellular inherent CO2-sensing and responding mechanisms in the treatment and prevention of certain illnesses that are related to the CO2 sensation and modulation in central and peripheral cells.

描述（申请人的摘要）：作为CO2传感的早期事件， 在脑干CO2化疗中已经证实了膜兴奋性 敏感的神经元，这似乎是由于突触的交替， 传递、转运蛋白活性和/或离子通道激活。的确， 包括我们在内的研究表明，K+通道是 控制这些化学敏感神经元的膜兴奋性。我们有 发现高碳酸血症引起的去极化被拮抗作用减弱 K+通道，而突触传递和其他几种离子的阻滞 渠道没有影响。随后，我们研究了这些CO2敏感的K+ 通道，并在这些通道中展示了一种新的CO2传感机制。这 机制依赖于固有的pH传感和通道门控过程， 内向整流钾离子通道，允许PCO 2水平的变化耦合 膜兴奋性的非扩张性变化。其中CO2敏感性K+ 通道，异聚Kir4.1-Kir5.1是特别有趣的。与 在生理pH水平下的线性工作范围，这些通道可以检测 高碳酸血症和低碳酸血症。再加上脑干特异性表达， 它们是潜在的CO2传感分子的非常有前途的候选者， 中央二氧化碳化学感受器很明显，详细的分子研究 这些K+通道中CO2传感的潜在机制可能产生重要的 二氧化碳化学感受的信息。因此，我们提出了实验来测试 三个具体的假设：1）异聚Kir4.1 -Kir5.1通道充当 CO2传感器2）Kir4.1 -Kir5.1通道特异性表达于 脑干神经元;和3）CO2增强化学敏感的细胞膜兴奋性 通过抑制Kir4.1 -Kir5.1通道来抑制神经元。这些研究的结果 不仅能提高我们对二氧化碳化学感受生理学的理解， 也可能有助于设计医疗干预措施， 治疗中细胞固有的CO2敏感和反应机制， 预防某些与二氧化碳感觉有关的疾病， 调节中枢和外周细胞。