Membrane Trafficking of Renal Potassium Channel

Summary

Principal Investigator: Chou Long Huang
Affiliation: University of Texas Southwestern Medical Center
Country: USA
Abstract: ROMK K+ channels play essential roles in the baseline potassium (K+) secretion in cortical collecting ducts (CCDs). As exit pathways for K+ secretion, the density of ROMK channels in CCDs is regulated by dietary K+ intake. Variations of K+ intake alter surface abundance of ROMK channels by affecting clathrin-coated vesicle- mediated endocytosis of channels. These adaptive changes are important for maintaining K+ homeostasis during variations of dietary K+ intake. Pseudohypoaldosteronism type II (PHA II) is an autosomal-dominant disease characterized by hypertension and hyperkalemia. Mutations of WNK1 and WNK4 cause PHA II. WNK (with-no-lysine [K]) kinases are serine-threonine protein kinases with an atypical placement of the catalytic lysine. Recent studies suggest that increased endocytosis of ROMK (thus, inhibition of ROMK) may contribute to hyperkalemia in PHA II caused by mutations of WNK1 and 4. How mutations of WNK kinases cause endocytosis of ROMK is not known. The long-term goal of our research is to study the molecular mechanism for membrane trafficking of ROMK channel and its importance in renal physiology and diseases. For the next funding period, we will study the mechanism by which WNKs cause endocytosis and how mutations of WNKs in PHA II lead to increased endocytosis of ROMK. We will further examine the mechanism and role of WNKs in the regulation of ROMK by dietary K+ intake. These studies will help us understand how kidney adjusts K+ excretion to meet the balance of K+ intake. Project Narrative: Kidney plays an essential role in the control of blood potassium level by excreting excess potassium. Abnormality in blood potassium level causes irregular heart beat, muscle weakness, and sudden death. Our studies aim to understand how kidney excretes potassium in physiological and diseased states.
Funding Period: ----------------2001 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms
    Ahmed Lazrak
    Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390 8856, USA
    Proc Natl Acad Sci U S A 103:1615-20. 2006
  2. ncbi Mechanism of regulation of renal ion transport by WNK kinases
    Chou Long Huang
    Department of Medicine, Division of Nephrology, UT Southwestern Medical Center, Dallas, Texas 75390 8856, USA
    Curr Opin Nephrol Hypertens 17:519-25. 2008
  3. pmc Extracellular potassium homeostasis: insights from hypokalemic periodic paralysis
    Chih Jen Cheng
    Department of Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX 75390 8859, USA
    Semin Nephrol 33:237-47. 2013
  4. pmc Kidney-specific WNK1 inhibits sodium reabsorption in the cortical thick ascending limb
    Chih Jen Cheng
    Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 8856, USA
    Am J Physiol Renal Physiol 303:F667-73. 2012
  5. pmc The Drosophila NKCC Ncc69 is required for normal renal tubule function
    Aylin R Rodan
    Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, USA
    Am J Physiol Cell Physiol 303:C883-94. 2012
  6. pmc Kidney-specific WNK1 regulates sodium reabsorption and potassium secretion in mouse cortical collecting duct
    Chih Jen Cheng
    Department of Medicine, Division of Nephrology, UT Southwestern Medical Center, Dallas, TX 75390, USA
    Am J Physiol Renal Physiol 304:F397-402. 2013
  7. pmc Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart
    Jian Xie
    Department of Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA
    Nat Commun 3:1238. 2012
  8. pmc WNK1 protein kinase regulates embryonic cardiovascular development through the OSR1 signaling cascade
    Jian Xie
    Department of Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390 8856, USA
    J Biol Chem 288:8566-74. 2013
  9. doi Clinical assessment of phosphorus status, balance and renal handling in normal individuals and in patients with chronic kidney disease
    Chou Long Huang
    Department of Internal Medicine, Clinical Research University of Texas, Southwestern Medical Center, Dallas, Texas 75390 8856, USA
    Curr Opin Nephrol Hypertens 22:452-8. 2013
  10. pmc Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1
    Seung Kuy Cha
    Departments of Medicine and Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 105:9805-10. 2008

Scientific Experts

  • S Susan Hedayati
  • Aylin R Rodan
  • Chou Long Huang
  • Chih Jen Cheng
  • Jian Xie
  • Seung Kuy Cha
  • Zhen Liu
  • Hao Ran Wang
  • Elizabeth Kuo
  • Sung Wan An
  • Shih Hua Lin
  • Sung Sen Yang
  • Makoto Kuro-o
  • Melanie H Cobb
  • Michel Baum
  • Joonho Yoon
  • Thao Truong
  • Tao Wu
  • Charles J Heise
  • Hiroshi Kurosu
  • Guocheng He
  • Ahmed Lazrak
  • Orson W Moe
  • Lutz Birnbaumer
  • Stephen C Cannon
  • Richard J Auchus
  • Yi Fen Lo
  • Seungwoo Chang
  • Yu Juei Hsu
  • Elliott M Ross
  • Steve Stippec
  • Bing E Xu
  • Yingming Zhao
  • Samarpita Sengupta
  • Staci L Deaton
  • Svetlana Earnest
  • Yu Chi Juang
  • Yingda Xu
  • Ivan K Huang
  • Ming Chang Hu
  • Ke Xu
  • Orson Moe
  • Ondine Cleaver
  • Kevin P Rosenblatt
  • Robert D Toto
  • Bernardo Ortega
  • Shao Kuei Huang
  • Leonard Craig

Detail Information

Publications31

  1. pmc Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms
    Ahmed Lazrak
    Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390 8856, USA
    Proc Natl Acad Sci U S A 103:1615-20. 2006
    ..Thus, KS-WNK1 is a physiological antagonist of long WNK1. Hyperkalemia in PHA II patients with PHA II mutations may be caused, at least partially, by increased expression of long WNK1 with or without decreased expression of KS-WNK1...
  2. ncbi Mechanism of regulation of renal ion transport by WNK kinases
    Chou Long Huang
    Department of Medicine, Division of Nephrology, UT Southwestern Medical Center, Dallas, Texas 75390 8856, USA
    Curr Opin Nephrol Hypertens 17:519-25. 2008
    ..This review summarizes recent advances in the understanding of the mechanism of regulation of renal ion transport by WNK kinases...
  3. pmc Extracellular potassium homeostasis: insights from hypokalemic periodic paralysis
    Chih Jen Cheng
    Department of Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX 75390 8859, USA
    Semin Nephrol 33:237-47. 2013
    ..These recent findings are reviewed. ..
  4. pmc Kidney-specific WNK1 inhibits sodium reabsorption in the cortical thick ascending limb
    Chih Jen Cheng
    Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 8856, USA
    Am J Physiol Renal Physiol 303:F667-73. 2012
    ..Thus KS-WNK1 inhibits Na(+) reabsorption in cTAL and mediates the inhibition of Na(+) reabsorption in the segment by a high-K diet...
  5. pmc The Drosophila NKCC Ncc69 is required for normal renal tubule function
    Aylin R Rodan
    Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, USA
    Am J Physiol Cell Physiol 303:C883-94. 2012
    ..Thus, Ncc69 plays an important role in transepithelial ion and fluid transport in the fly renal tubule and is a target for regulation in antidiuretic states...
  6. pmc Kidney-specific WNK1 regulates sodium reabsorption and potassium secretion in mouse cortical collecting duct
    Chih Jen Cheng
    Department of Medicine, Division of Nephrology, UT Southwestern Medical Center, Dallas, TX 75390, USA
    Am J Physiol Renal Physiol 304:F397-402. 2013
    ..In addition, KS-WNK1 plays a role in regulating Na(+) transport in the CCD...
  7. pmc Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart
    Jian Xie
    Department of Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA
    Nat Commun 3:1238. 2012
    ..These results provide a new perspective on the pathogenesis of cardiomyopathies and open new avenues for treatment of the disease...
  8. pmc WNK1 protein kinase regulates embryonic cardiovascular development through the OSR1 signaling cascade
    Jian Xie
    Department of Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390 8856, USA
    J Biol Chem 288:8566-74. 2013
    ..These results indicate that WNK1 activation of the OSR1 signaling cascade is an essential pathway that regulates angiogenesis and cardiac formation during mouse embryo development...
  9. doi Clinical assessment of phosphorus status, balance and renal handling in normal individuals and in patients with chronic kidney disease
    Chou Long Huang
    Department of Internal Medicine, Clinical Research University of Texas, Southwestern Medical Center, Dallas, Texas 75390 8856, USA
    Curr Opin Nephrol Hypertens 22:452-8. 2013
    ..The purpose of this review is to clarify the above concepts and discuss the utility of the currently available tests to assess phosphorus disorders...
  10. pmc Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1
    Seung Kuy Cha
    Departments of Medicine and Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 105:9805-10. 2008
    ..This action of Klotho represents a novel mechanism for regulation of the activity of cell-surface glycoproteins and likely contributes to maintenance of calcium balance by Klotho...
  11. pmc Domains of WNK1 kinase in the regulation of ROMK1
    Hao Ran Wang
    Division of Nephrology, Department of Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
    Am J Physiol Renal Physiol 295:F438-45. 2008
    ..Thus, multiple intra- and/or intermolecular interactions of WNK1 domains are at play for regulation of ROMK1 by WNK1...
  12. ncbi Mechanisms of disease: WNK-ing at the mechanism of salt-sensitive hypertension
    Chou Long Huang
    Division of Nephrology, UT Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390 8856, USA
    Nat Clin Pract Nephrol 3:623-30. 2007
    ..Here, we review the role of dietary K(+) deficiency in the pathogenesis of salt-sensitive hypertension and summarize recent findings indicating that WNK1 might mediate renal Na(+) retention and hypertension in K(+) deficiency...
  13. ncbi Complex roles of PIP2 in the regulation of ion channels and transporters
    Chou Long Huang
    UT Southwestern Medical Center, Dept of Medicine, 5323 Harry Hines Blvd, Dallas, TX 75390 8856, USA
    Am J Physiol Renal Physiol 293:F1761-5. 2007
    ..Here, I briefly review several past and recent studies to illustrate the complexities and raise outstanding questions for future studies...
  14. ncbi Mechanism of hypokalemia in magnesium deficiency
    Chou Long Huang
    UT Southwestern Medical Center, Department of Medicine, 5323 Harry Hines Boulevard, Dallas, TX 75390 8856, USA
    J Am Soc Nephrol 18:2649-52. 2007
    ..Magnesium deficiency alone, however, does not necessarily cause hypokalemia. An increase in distal sodium delivery or elevated aldosterone levels may be required for exacerbating potassium wasting in magnesium deficiency...
  15. ncbi WNKs: protein kinases with a unique kinase domain
    Chou Long Huang
    Department of Medicine, University of Texas, Southwestern Medical Center, Dallas, Texas 75390, USA
    Exp Mol Med 39:565-73. 2007
    ..Here, we review roles of WNK kinases in the regulation of ion balance, cell signaling, survival, and proliferation, and embryonic organ development...
  16. pmc Intersectin links WNK kinases to endocytosis of ROMK1
    Guocheng He
    Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390 8856, USA
    J Clin Invest 117:1078-87. 2007
    ..Disease-causing WNK4 mutations enhanced interactions of WNK4 with ITSN and ROMK1, leading to increased endocytosis of ROMK1. These results provide a molecular mechanism for stimulation of endocytosis of ROMK1 by WNK kinases...
  17. ncbi Probing the effects of phosphoinositides on ion channels
    Chou Long Huang
    Department of Medicine, UT Southwestern Medical Center, Dallas, TX, USA
    Methods Mol Biol 337:81-7. 2006
    ..Discussed here are several methods for studying regulation of ion channels by phospholipids...
  18. ncbi Role of with-no-lysine [K] kinases in the pathogenesis of Gordon's syndrome
    Jian Xie
    Department of Medicine, Room J5 104, MC 8856, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390 8856, USA
    Pediatr Nephrol 21:1231-6. 2006
    ..Here, we review the pathogenesis of PHA II based on current understanding of the actions of WNK1 and WNK4 on Na+ and K+ handling in the renal distal tubule...
  19. doi WNK kinases and essential hypertension
    Chou Long Huang
    Department of Medicine, Division of Nephrology, UT Southwestern Medical Center, Dallas, Texas 75390 8856, USA
    Curr Opin Nephrol Hypertens 17:133-7. 2008
    ..The present review summarizes recent literature and discusses the potential roles of WNKs in the pathogenesis of essential hypertension...
  20. pmc WNK1 promotes PIPâ‚‚ synthesis to coordinate growth factor and GPCR-Gq signaling
    Sung Wan An
    Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Curr Biol 21:1979-87. 2011
    ..WNK1 protein kinase is known to regulate ion homeostasis and cause hypertension when expression is increased by gene mutations. However, its signaling functions remain largely elusive...
  21. pmc Association of urinary sodium/potassium ratio with blood pressure: sex and racial differences
    S Susan Hedayati
    Renal Section, Medical Service, Veterans Affairs North Texas Health Care System, Dallas, TX 75216 7167, USA
    Clin J Am Soc Nephrol 7:315-22. 2012
    ..Previous studies reporting an association between high BP and high sodium and low potassium intake or urinary sodium/potassium ratio (U[Na(+)]/[K(+)]) primarily included white men and did not control for cardiovascular risk factors...
  22. pmc Identification and functional characterization of Kir2.6 mutations associated with non-familial hypokalemic periodic paralysis
    Chih Jen Cheng
    Department of Medicine, Division of Nephrology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390 8856, USA
    J Biol Chem 286:27425-35. 2011
    ..6 predisposes the sarcolemma to hypokalemia-induced paradoxical depolarization during attacks, which in turn leads to Na(+) channel inactivation and inexcitability of muscles...
  23. pmc Activation of PI3-kinase stimulates endocytosis of ROMK via Akt1/SGK1-dependent phosphorylation of WNK1
    Chih Jen Cheng
    Department of Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 8856, USA
    J Am Soc Nephrol 22:460-71. 2011
    ..Taken together, these results suggest that PI3K-activating hormones inhibit ROMK by enhancing its endocytosis via a mechanism that involves phosphorylation of WNK1 by Akt1 and SGK1...
  24. pmc Recent advances in distal tubular potassium handling
    Aylin R Rodan
    Division of Nephrology, Department of Medicine, UT, USA
    Am J Physiol Renal Physiol 300:F821-7. 2011
    ..We also discuss outstanding questions and propose working models for future investigation...
  25. pmc Downregulation of NCC and NKCC2 cotransporters by kidney-specific WNK1 revealed by gene disruption and transgenic mouse models
    Zhen Liu
    Division of Nephrology, Department of Medicine, UT Southwestern Medical Center, Dallas, TX 75390 8856, USA
    Hum Mol Genet 20:855-66. 2011
    ..Thus, KS-WNK1 is a negative regulator of NCC and NKCC2 in vivo and plays an important role in the control of Na(+) homeostasis and blood pressure. These results have important implications to the pathogenesis of PHA2 with WNK1 mutations...
  26. pmc Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members
    Charles J Heise
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9041, USA
    J Biol Chem 285:25161-7. 2010
    ..Further evidence for the importance of WNK1 in this process comes from the ability of Nedd4-2 to bind to WNK1 and the finding that endogenous SGK1 has reduced activity if WNK1 is knocked down by small interfering RNA...
  27. pmc Distal potassium handling based on flow modulation of maxi-K channel activity
    Aylin R Rodan
    Division of Nephrology, Department of Medicine, UT Southwestern Medical Center, Dallas, Texas 75390 8856, USA
    Curr Opin Nephrol Hypertens 18:350-5. 2009
    ..This review considers several human disorders characterized by hypokalemia and hyperkalemia, as well as mouse models of these disorders, and the mechanisms by which ROMK and maxi-K may be dysregulated...
  28. pmc Regulation of renal outer medullary potassium channel and renal K(+) excretion by Klotho
    Seung Kuy Cha
    Department of Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX 75390 8856, USA
    Mol Pharmacol 76:38-46. 2009
    ..Intravenous administration of KLe increases the level of Klotho in urine and increases urinary excretion of K(+). These results suggest that Klotho may have a broader function in the regulation of ion transport in the kidney...
  29. pmc Regulation of ROMK channel and K+ homeostasis by kidney-specific WNK1 kinase
    Zhen Liu
    Department of Medicine Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 8856, USA
    J Biol Chem 284:12198-206. 2009
    ..Thus, KS-WNK1 is an important physiological regulator of renal K(+) excretion, likely through its effects on the ROMK1 channel...
  30. pmc Endothelial-specific expression of WNK1 kinase is essential for angiogenesis and heart development in mice
    Jian Xie
    Department of Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 8856, USA
    Am J Pathol 175:1315-27. 2009
    ....