Regulation of Lung Sodium Channels

肺钠通道的调节

• 批准号: 6327062
• 负责人: LUCKY JAIN
• 金额: $ 30.47万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6327062
• 关键词: hormone regulation /control mechanism; laboratory rat; lung; oxygen tension; phosphorylation; protein isoforms; protein structure function; respiratory epithelium; sodium channel; steroid hormone; voltage /patch clamp

Alveolar fluid clearance in the developing and mature lungs is believed to be mediated, in part, by amiloride-recorded from distal lung epithelia were different from channels reported from other Na+ transporting epithelia expressing ENaC. Preliminary experiments from this laboratory show that, when grown under appropriate culture conditions, rat alveolar type II (ATII) cells express three distinct types of cation channels that are capable of transporting Na+. The highly selective and non selective cation channels appear to belong to the ENaC family of Na+ channels, but bear striking differences in their biophysical properties, and in their regulation by signal transduction pathways, including those working through protein kinases A, G, and C. It is hypothesized that lung alveolar environment, including steroids and oxygen, is responsible for selective expression of highly selective and non selective cation channels in ATII cells, and this is achieved through different arrangements of ENaC subunits. Further, it is proposed that signal transduction pathways mediated by protein kinases A, G, and C regulate the expression and activity of both the highly selective, and non selective cation channels. These questions will be addressed by combining the use of patch clamp techniques and molecular biological approaches to characterize Na+ permeant channels in ATII cells. There are three specific aims to this proposal. The first aim is to contrast the biophysical properties of Na+ channels in ATII ells at the single channel level, and to establish their relationship to the cloned ENaC subunits. The second aim is to investigate conditions, including exposure to steroid hormones and differing oxygen tension, that lead to differences in the density of non selective channels and highly selective channels in ATII cells. The third aim is to contrast the regulation of highly selective and non-selective cation channels in ATII cells by phosphorylation and dephosphorylation. These experiments will improve our understanding of how lungs modulate alveolar fluid absorption, and help it devising therapeutic strategies to improve the process.

据信，发育中和成熟的肺中的肺泡流体清除率部分是由远端肺上皮录制的Amiloride录制的部分与来自其他表达eNAC的上皮的Na+转运上皮的通道不同。该实验室的初步实验表明，在适当的培养条件下生长时，大鼠肺泡II型（ATII）细胞表达能够运输Na+的三种不同类型的阳离子通道。高度选择性和非选择性阳离子通道似乎属于Na+通道的ENAC家族，但在其生物物理性能中遇到了显着差异，以及通过信号转导途径进行调控，包括通过蛋白激酶A，G和C进行的。该肺活量和氧气的高度选择性，包​​括肺肺泡环境和氧气的高度选择性，包​​括在内这是通过ENAC亚基的不同安排来实现的。此外，有人提出，由蛋白激酶A，G和C介导的信号转导途径调节高度选择性和非选择性阳离子通道的表达和活性。这些问题将通过结合使用贴片夹技术和分子生物学方法来表征ATII细胞中Na+ Pereant通道的使用来解决这些问题。该提案有三个具体的目标。第一个目的是对比单个通道水平的ATII ELL中Na+通道的生物物理特性，并建立与克隆的ENAC亚基的关系。第二个目的是研究条件，包括暴露于类固醇激素和不同的氧张力，从而导致非选择性通道的密度差异和ATII细胞中高度选择性通道的差异。第三个目的是通过磷酸化和去磷酸化来对比ATII细胞中高度选择性和非选择性阳离子通道的调节。这些实验将提高我们对肺部如何调节肺泡液的吸收的理解，并帮助其设计治疗策略以改善过程。