ROMK (Kir 1.1, product of he 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 a familiar disease of hyperkalemia and hypertension. This application builds on our discoveries that a novel variant of a "NPXY"-type signal in ROMK serves as a recognition site for binding to ARH, a member of a new class of clathrin-adaptor proteins, and this interaction marks channels for rapid endocytosis and eventual lysosomal degradation. Knockout mice, lacking ARH, exhibit an altered renal ROMK response to dietary potassium intake. To carry these breakthrough observations toward a completely new understanding of how potassium balance is achieved, we outline plans to: 1) conduct a complete system-to-molecule phenotypic characterization of the ARH knockout mouse to critically evaluate the physiological consequence of ARH-dependent ROMK endocytosis, 2) explore the involvement of a novel signaling pathway that physiologically regulates ARH, 3) elucidate the molecular mechanism by which WNK-1 stimulates ARH-dependent endocytosis and 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.
ROMK potassium channels are tightly regulated in the kidney by membrane trafficking mechanisms, ensuring that potassium is precisely excreted in accord with the demands of potassium balance. Disruption of ROMK channel trafficking and surface expression can, in fact, have devastating consequences on salt and mineral balance. Despite its importance, a long-standing and fundamental question in cell biology and physiology has been how the number and location of these membrane proteins are precisely controlled. In the present proposal, we elucidate the molecular mechanisms driving membrane trafficking of these channels in health and study what may happen when these processes go awry in disease. Thus, 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.
|Lee, Chunsik; Liu, Anguo; Miranda-Ribera, Alba et al. (2014) NEU1 sialidase regulates the sialylation state of CD31 and disrupts CD31-driven capillary-like tube formation in human lung microvascular endothelia. J Biol Chem 289:9121-35|
|Kolb, Alexander R; Needham, Patrick G; Rothenberg, Cari et al. (2014) ESCRT regulates surface expression of the Kir2.1 potassium channel. Mol Biol Cell 25:276-89|
|Welling, Paul A (2014) Rare mutations in renal sodium and potassium transporter genes exhibit impaired transport function. Curr Opin Nephrol Hypertens 23:1-8|
|Welling, Paul A (2013) Regulation of potassium channel trafficking in the distal nephron. Curr Opin Nephrol Hypertens 22:559-65|
|Subramanya, Arohan R; Welling, Paul A (2011) Toward an understanding of hypertension resistance. Am J Physiol Renal Physiol 300:F838-9|
|Ma, Donghui; Taneja, Tarvinder Kaur; Hagen, Brian M et al. (2011) Golgi export of the Kir2.1 channel is driven by a trafficking signal located within its tertiary structure. Cell 145:1102-15|
|Wade, James B; Fang, Liang; Coleman, Richard A et al. (2011) Differential regulation of ROMK (Kir1.1) in distal nephron segments by dietary potassium. Am J Physiol Renal Physiol 300:F1385-93|
|Welling, Paul A; Chang, Yen-Pei C; Delpire, Eric et al. (2010) Multigene kinase network, kidney transport, and salt in essential hypertension. Kidney Int 77:1063-9|
|Frindt, Gustavo; Palmer, Lawrence G (2010) Effects of dietary K on cell-surface expression of renal ion channels and transporters. Am J Physiol Renal Physiol 299:F890-7|
|Welling, Paul A; Ho, Kevin (2009) A comprehensive guide to the ROMK potassium channel: form and function in health and disease. Am J Physiol Renal Physiol 297:F849-63|
Showing the most recent 10 out of 28 publications