Molecular Mechanism of ROMK Channel Function

ROMK通道功能的分子机制

基本信息

批准号：
9897412
负责人：
Paul A Welling
金额：
$ 50.62万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-10-05 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9897412
关键词：
Adaptor Signaling Protein Address Aldosterone Automobile Driving Binding Sites Cell physiology Cellular biology Chlorides Clathrin Clathrin Adaptors Data Dietary Potassium Disease Distal Electrophysiology (science)Endocytosis Ensure Equilibrium Excretory function Family Funding Goals Gordon syndrome Health Homeostasis Hypokalemia Image In Vitro KCNJ1 gene Kidney Kidney Diseases Knock-in Mouse Knock-out Knockout Mice Laboratories Life Location Lysosomes MAPK7 gene Mediating Membrane Membrane Proteins Minerals Molecular Molecular Genetics Mus Mutate Nephrons Online Mendelian Inheritance In Man Pathway interactions Phenotype Phosphotransferases Physiological Physiology Play Potassium Potassium Channel Potassium Deficiency Principal Investigator Process Proteins Publishing Recycling Role Route Signal Transduction Sodium Sodium Chloride Surface System Testing Time Translating Type II Pseudohypoaldosteronism Variant Work apical membrane driving force epithelial Na+ channel extracellular familial hyperkalemic hypertension genome wide screen hyperkalemia in vivo insight interdisciplinary approach kidney epithelial cell member mouse model novel programs recruit secretion process trafficking urinary voltage

项目摘要

ROMK (Kir 1.1, product of the KCNJ1 gene) channels in the kidney are exquisitely regulated to adjust renal potassium excretion and maintain potassium balance. Clathrin-dependent endocytosis plays a critical role, limiting urinary potassium loss in potassium deficiency. In renal disease, aberrant ROMK endocytosis may contribute to potassium retention and life-threatening hyperkalemia. Available evidence indicates ROMK endocytosis is stimulated by WNKs, kinases that are mutated in Familial Hyperkalemic and Hypertension (FHHt). This application builds on our recent discoveries that: 1) Low potassium directly stimulates ROMK endocytosis in the distal nephron, 2) WNK stimulates ROMK endocytosis by phosphorylating the clathrin-adaptor, ARH, 3) NEDD4 Family of Interacting Proteins, NDFIP1 and 2, interact with ROMK to control post-endocytic processing of the channel. To carry these breakthrough observations toward a completely new understanding of how potassium balance is achieved, we outline plans to: 1) Define the mechanism by which potassium directly regulates ROMK endocytosis; 2) Explore the involvement of this pathway in a mouse model of FHHt, 3) Elucidate the molecular mechanism by which NDFIP1 and NDFIP2 control post-endocytic routing of ROMK to the lysosome. The studies should provide novel insights into the molecular basis of renal K handling and K homeostasis in health and disease while illuminating fundamental mechanisms of membrane protein targeting in the kidney.

肾脏中的 ROMK（Kir 1.1，KCNJ1 基因的产物）通道是精细调节，调节肾钾排泄，维持钾平衡。网格蛋白依赖性内吞作用起着关键作用，限制尿钾钾缺乏造成的损失。在肾脏疾病中，ROMK 内吞作用异常可能导致钾潴留和危及生命的高钾血症。现有证据表明 ROMK 内吞作用受到 WNK 的刺激，WNK 是在家族性高钾血症和高血压（FHHt）。该应用程序建立在我们最近的研究发现：1) 低钾直接刺激远端 ROMK 内吞作用肾单位，2) WNK 通过磷酸化网格蛋白接头来刺激 ROMK 内吞作用， ARH，3) NEDD4 相互作用蛋白家族，NDFIP1 和 2，与 ROMK 相互作用控制通道的内吞后处理。为了实现这些突破观察对钾平衡的全新理解为了实现这一目标，我们概述了以下计划： 1) 明确钾直接作用的机制调节 ROMK 内吞作用； 2) 探索该通路在小鼠中的参与情况 FHHt模型，3）阐明NDFIP1和NDFIP2的分子机制控制 ROMK 到溶酶体的内吞后路由。研究应提供对健康中肾脏钾处理和钾稳态的分子基础的新见解和疾病，同时阐明膜蛋白靶向的基本机制在肾脏。