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.
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.
| Mackie, Timothy D; Kim, Bo-Young; Subramanya, Arohan R et al. (2018) The endosomal trafficking factors CORVET and ESCRT suppress plasma membrane residence of the renal outer medullary potassium channel (ROMK). J Biol Chem 293:3201-3217 |
| Welling, Paul A (2018) WNKs on the Fly. J Am Soc Nephrol 29:1347-1349 |
| Harris, Autumn N; Grimm, P Richard; Lee, Hyun-Wook et al. (2018) Mechanism of Hyperkalemia-Induced Metabolic Acidosis. J Am Soc Nephrol 29:1411-1425 |
| West, Crystal A; Welling, Paul A; West Jr, David A et al. (2018) Renal and colonic potassium transporters in the pregnant rat. Am J Physiol Renal Physiol 314:F251-F259 |
| Grimm, P Richard; Coleman, Richard; Delpire, Eric et al. (2017) Constitutively Active SPAK Causes Hyperkalemia by Activating NCC and Remodeling Distal Tubules. J Am Soc Nephrol 28:2597-2606 |
| Welling, Paul A (2016) Roles and Regulation of Renal K Channels. Annu Rev Physiol 78:415-35 |
| Li, Xiangming; Ortega, Bernardo; Kim, Boyoung et al. (2016) A Common Signal Patch Drives AP-1 Protein-dependent Golgi Export of Inwardly Rectifying Potassium Channels. J Biol Chem 291:14963-72 |
| Wade, James B; Liu, Jie; Coleman, Richard et al. (2015) SPAK-mediated NCC regulation in response to low-K+ diet. Am J Physiol Renal Physiol 308:F923-31 |
| Grimm, P Richard; Lazo-Fernandez, Yoskaly; Delpire, Eric et al. (2015) Integrated compensatory network is activated in the absence of NCC phosphorylation. J Clin Invest 125:2136-50 |
| 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 |
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