KIR channel modulations in hypercapnic acidosis

描述(申请人摘要)：作为二氧化碳传感的早期事件，变化 在脑干二氧化碳化疗中证实了膜上的兴奋性 敏感神经元，似乎是突触交替的结果 传输、转运体活性和/或离子通道激活。的确， 包括我们在内的研究表明，K通道是 控制这些化疗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可被拮抗作用减弱 K通道，同时阻断突触传递和其他几种离子 频道没有任何影响。此后，我们研究了这些对二氧化碳敏感的K 并在这些通道中展示了一种新颖的二氧化碳传感机制。这 机制依赖于固有的pH传感和通道门控过程 内向整流器K通道，允许耦合PCO2水平的变化 导致膜兴奋性的非扩张性改变。在这些对二氧化碳敏感的K 通道中，异构体Kir4.1-Kir5.1特别有趣。使用一个 在生理pH水平下的线性工作范围，这些通道可以检测到 高碳酸血症和低碳酸血症。这些基因加上它们脑干特有的表达，使得 它们是潜在的二氧化碳传感分子的极有希望的候选者 中央二氧化碳化学感受器。显然，对分子的详细研究 这些K通道中二氧化碳感应的潜在机制可能会产生重要的 二氧化碳化学感受信息。因此，我们提出了一些实验来测试 三个具体的假设：1)异构体Kir4.1-Kir5.1通道作为 二氧化碳传感器2)Kir4.1-Kir5.1通道具体表示为 脑干神经元；3)CO2增强化疗敏感性的膜兴奋性 通过抑制Kir4.1-Kir5.1通道来抑制神经元。这些研究的结果 不仅将提高我们对二氧化碳化学接受生理学的理解，而且 也可以通过操纵这些来帮助医疗干预的设计 细胞固有的二氧化碳感应和反应机制在治疗和 预防某些与二氧化碳感觉有关的疾病和 中央和外周细胞的调制。

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.