Molecular Mechanism of ROMK Channel Function

ROMK通道功能的分子机制

• 批准号: 10048980
• 负责人: Paul A Welling
• 金额: $ 19.54万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-05 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10048980
• 关键词: Molecular; Mechanism; ROMK; Channel; Function

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，KCNJ 1基因的产物）通道是 精细调节肾脏排钾，维持钾 平衡网格蛋白依赖的内吞作用起着关键作用，限制尿钾 钾缺乏的损失。在肾脏疾病中，异常的ROMK内吞作用可能 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是一种突变的激酶， 家族性高钾血症和高血压（FHHt）。这个应用程序建立在我们最近的 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-衔接子刺激ROMK内吞作用， ARH，3）NEDD 4相互作用蛋白家族，NDFIP 1和2，与ROMK相互作用， 控制通道的内吞后加工。为了实现这些突破 对钾平衡的全新理解的观察 实现，我们概述计划：1）定义钾直接 调节ROMK内吞作用; 2）探索小鼠中该途径的参与 3）阐明NDFIP 1和NDFIP 2与FHHt相互作用的分子机制 控制ROMK到溶酶体的内吞后路由。研究应提供 对健康肾脏钾处理和钾稳态的分子基础的新见解 同时阐明膜蛋白靶向的基本机制 在肾脏中。