Molecular Mechanism of ROMK Channel Function

点击翻译按钮获取中文摘要

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.