The salt-wasting phenotype of EAST syndrome, a disease with multifaceted symptoms linked to the KCNJ10 K+ channel

  • Sascha Bandulik
  • Katharina Schmidt
  • Detlef Bockenhauer
  • Anselm A. Zdebik
  • Evelyn Humberg
  • Robert Kleta
  • Richard WarthEmail author
  • Markus Reichold
Invited Review


Mutations in the K+ channel gene KCNJ10 (Kir4.1) cause the autosomal recessive EAST syndrome which is characterized by epilepsy, ataxia, sensorineural deafness, and a salt-wasting tubulopathy. The renal salt-wasting pathology of EAST syndrome is caused by transport defects in the distal convoluted tubule where KCNJ10 plays a pivotal role as a basolateral K+ channel. This review on EAST syndrome outlines the molecular aspects of the physiology and pathophysiology of KCNJ10 in the distal convoluted tubule.


Kir4.1 Salt-losing syndrome Distal convoluted tubule Channelopathy Potassium channel Kidney K channel Transport Epilepsy 



Distal convoluted tubule


Early distal convoluted tubule


Late distal convoluted tubule


Connecting tubule


NaCl co-transporter


Na+2ClK+ co-transporter


Ca2+-sensing receptor


Epilepsy, ataxia, sensorineural deafness, and a salt-wasting tubulopathy


Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance



The study was supported by the Deutsche Forschungsgemeinschaft, SFB699, to MR and RW. DB is supported by the special trustees of Great Ormond Street Hospital.


  1. 1.
    Adalat S, Woolf AS, Johnstone KA, Wirsing A, Harries LW, Long DA, Hennekam RC, Ledermann SE, Rees L, van't Hoff W, Marks SD, Trompeter RS, Tullus K, Winyard PJ, Cansick J, Mushtaq I, Dhillon HK, Bingham C, Edghill EL, Shroff R, Stanescu H, Ryffel GU, Ellard S, Bockenhauer D (2009) HNF1B mutations associate with hypomagnesemia and renal magnesium wasting. J Am Soc Nephrol 20(5):1123–1131PubMedCrossRefGoogle Scholar
  2. 2.
    Bettinelli A, Bianchetti MG, Girardin E, Caringella A, Cecconi M, Appiani AC, Pavanello L, Gastaldi R, Isimbaldi C, Lama G (1992) Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. J Pediatr 120(1):38–43PubMedCrossRefGoogle Scholar
  3. 3.
    Bichet D, Haass FA, Jan LY (2003) Merging functional studies with structures of inward-rectifier K(+) channels. Nat Rev Neurosci 4(12):957–967PubMedCrossRefGoogle Scholar
  4. 4.
    Bindels RJ (2010) 2009 Homer W. Smith award: Minerals in motion: from new ion transporters to new concepts. J Am Soc Nephrol 21(8):1263–1269PubMedCrossRefGoogle Scholar
  5. 5.
    Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, Tobin J, Lieberer E, Sterner C, Landoure G, Arora R, Sirimanna T, Thompson D, Cross JH, van't Hoff W, Al Masri O, Tullus K, Yeung S, Anikster Y, Klootwijk E, Hubank M, Dillon MJ, Heitzmann D, Arcos-Burgos M, Knepper MA, Dobbie A, Gahl WA, Warth R, Sheridan E, Kleta R (2009) Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl J Med 360(19):1960–1970PubMedCrossRefGoogle Scholar
  6. 6.
    Bockenhauer D, Stanescu H, Kleta R (2009) Author reply to correspondence by Shi M and Zhao G: the EAST syndrome and KCNJ10 mutations. N Engl J Med 361(6):630–631 (correspondence)CrossRefGoogle Scholar
  7. 7.
    Casamassima M, D'Adamo MC, Pessia M, Tucker SJ (2003) Identification of a heteromeric interaction that influences the rectification, gating, and pH sensitivity of Kir4.1/Kir5.1 potassium channels. J Biol Chem 278(44):43533–43540PubMedCrossRefGoogle Scholar
  8. 8.
    Chabardes-Garonne D, Mejean A, Aude JC, Cheval L, Di SA, Gaillard MC, Imbert-Teboul M, Wittner M, Balian C, Anthouard V, Robert C, Segurens B, Wincker P, Weissenbach J, Doucet A, Elalouf JM (2003) A panoramic view of gene expression in the human kidney. Proc Natl Acad Sci USA 100(23):13710–13715PubMedCrossRefGoogle Scholar
  9. 9.
    Chever O, Djukic B, McCarthy KD, Amzica F (2010) Implication of kir4.1 channel in excess potassium clearance: an in vivo study on anesthetized glial-conditional kir4.1 knock-out mice. J Neurosci 30(47):15769–15777PubMedCrossRefGoogle Scholar
  10. 10.
    Chubanov V, Waldegger S, Schnitzler M, Vitzthum H, Sassen MC, Seyberth HW, Konrad M, Gudermann T (2004) Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia. Proc Natl Acad Sci USA 101(9):2894–2899PubMedCrossRefGoogle Scholar
  11. 11.
    Dai LJ, Ritchie G, Kerstan D, Kang HS, Cole DE, Quamme GA (2001) Magnesium transport in the renal distal convoluted tubule. Physiol Rev 81(1):51–84PubMedGoogle Scholar
  12. 12.
    Djukic B, Casper KB, Philpot BD, Chin LS, McCarthy KD (2007) Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation. J Neurosci 27(42):11354–11365PubMedCrossRefGoogle Scholar
  13. 13.
    Estevez R, Boettger T, Stein V, Birkenhager R, Otto E, Hildebrandt F, Jentsch TJ (2001) Barttin is a Cl channel beta-subunit crucial for renal Cl reabsorption and inner ear K+ secretion. Nature 414(6863):558–561PubMedCrossRefGoogle Scholar
  14. 14.
    Fakler B, Schultz JH, Yang J, Schulte U, Brandle U, Zenner HP, Jan LY, Ruppersberg JP (1996) Identification of a titratable lysine residue that determines sensitivity of kidney potassium channels (ROMK) to intracellular pH. EMBO J 15(16):4093–4099PubMedGoogle Scholar
  15. 15.
    Friedman PA (1998) Codependence of renal calcium and sodium transport. Annu Rev Physiol 60:179–197PubMedCrossRefGoogle Scholar
  16. 16.
    Gamba G, Saltzberg SN, Lombardi M, Miyanoshita A, Lytton J, Hediger MA, Brenner BM, Hebert SC (1993) Primary structure and functional expression of a cDNA encoding the thiazide-sensitive, electroneutral sodium-chloride cotransporter. Proc Natl Acad Sci USA 90(7):2749–2753PubMedCrossRefGoogle Scholar
  17. 17.
    Gitelman HJ, Graham JB, Welt LG (1966) A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 79:221–235PubMedGoogle Scholar
  18. 18.
    Glaudemans B, Knoers NV, Hoenderop JG, Bindels RJ (2010) New molecular players facilitating Mg(2+) reabsorption in the distal convoluted tubule. Kidney Int 77(1):17–22PubMedCrossRefGoogle Scholar
  19. 19.
    Glaudemans B, van der Wijst J, Scola RH, Lorenzoni PJ, Heister A, van der Kemp AW, Knoers NV, Hoenderop JG, Bindels RJ (2009) A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia. J Clin Invest 119(4):936–942PubMedCrossRefGoogle Scholar
  20. 20.
    Greger R, Velazquez H (1987) The cortical thick ascending limb and early distal convoluted tubule in the urinary concentrating mechanism. Kidney Int 31(2):590–596PubMedCrossRefGoogle Scholar
  21. 21.
    Groenestege WM, Thebault S, van der Wijst J, van den Berg D, Janssen R, Tejpar S, Van Den Heuvel LP, van CE H, JG KNV, Bindels RJ (2007) Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J Clin Invest 117(8):2260–2267PubMedCrossRefGoogle Scholar
  22. 22.
    Ho K, Nichols CG, Lederer WJ, Lytton J, Vassilev PM, Kanazirska MV, Hebert SC (1993) Cloning and expression of an inwardly rectifying ATP-regulated potassium channel. Nature 362(6415):31–38PubMedCrossRefGoogle Scholar
  23. 23.
    Hoenderop JG, Nilius B, Bindels RJ (2005) Calcium absorption across epithelia. Physiol Rev 85(1):373–422PubMedCrossRefGoogle Scholar
  24. 24.
    Hofer AM, Brown EM (2003) Extracellular calcium sensing and signalling. Nat Rev Mol Cell Biol 4(7):530–538PubMedCrossRefGoogle Scholar
  25. 25.
    Huang CL, Feng S, Hilgemann DW (1998) Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma. Nature 391(6669):803–806PubMedCrossRefGoogle Scholar
  26. 26.
    Huang C, Miller RT (2010) Novel Ca receptor signaling pathways for control of renal ion transport. Curr Opin Nephrol Hypertens 19(1):106–112PubMedCrossRefGoogle Scholar
  27. 27.
    Huang C, Sindic A, Hill CE, Hujer KM, Chan KW, Sassen M, Wu Z, Kurachi Y, Nielsen S, Romero MF, Miller RT (2007) Interaction of the Ca2+-sensing receptor with the inwardly rectifying potassium channels Kir4.1 and Kir4.2 results in inhibition of channel function. Am J Physiol Ren Physiol 292(3):F1073–F1081CrossRefGoogle Scholar
  28. 28.
    International Collaborative Study Group for Bartter-like Syndromes (1997) Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity. International Collaborative Study Group for Bartter-Like Syndromes. Hum Mol Genet 6(1):17–26CrossRefGoogle Scholar
  29. 29.
    Ito M, Inanobe A, Horio Y, Hibino H, Isomoto S, Ito H, Mori K, Tonosaki A, Tomoike H, Kurachi Y (1996) Immunolocalization of an inwardly rectifying K+ channel, K(AB)-2 (Kir4.1), in the basolateral membrane of renal distal tubular epithelia. FEBS Lett 388(1):11–15PubMedCrossRefGoogle Scholar
  30. 30.
    Kahle KT, Wilson FH, Leng Q, Lalioti MD, O'Connell AD, Dong K, Rapson AK, MacGregor GG, Giebisch G, Hebert SC, Lifton RP (2003) WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion. Nat Genet 35(4):372–376PubMedCrossRefGoogle Scholar
  31. 31.
    Kahle KT, Wilson FH, Lifton RP (2005) Regulation of diverse ion transport pathways by WNK4 kinase: a novel molecular switch. Trends Endocrinol Metab 16(3):98–103PubMedCrossRefGoogle Scholar
  32. 32.
    Kleta R, Bockenhauer D (2006) Bartter syndromes and other salt-losing tubulopathies. Nephron Physiol 104(2):p73–p80PubMedCrossRefGoogle Scholar
  33. 33.
    Koefoed-Johnsen V, Ussing HH (1958) The nature of the frog skin potential. Acta Physiol Scand 42(3–4):298–308PubMedCrossRefGoogle Scholar
  34. 34.
    Kofuji P, Biedermann B, Siddharthan V, Raap M, Iandiev I, Milenkovic I, Thomzig A, Veh RW, Bringmann A, Reichenbach A (2002) Kir potassium channel subunit expression in retinal glial cells: implications for spatial potassium buffering. Glia 39(3):292–303PubMedCrossRefGoogle Scholar
  35. 35.
    Kofuji P, Newman EA (2004) Potassium buffering in the central nervous system. Neuroscience 129(4):1045–1056PubMedCrossRefGoogle Scholar
  36. 36.
    Kramer BK, Bergler T, Stoelcker B, Waldegger S (2008) Mechanisms of disease: the kidney-specific chloride channels ClCKA and ClCKB, the Barttin subunit, and their clinical relevance. Nat Clin Pract Nephrol 4(1):38–46PubMedCrossRefGoogle Scholar
  37. 37.
    Lachheb S, Cluzeaud F, Bens M, Genete M, Hibino H, Lourdel S, Kurachi Y, Vandewalle A, Teulon J, Paulais M (2008) Kir4.1/Kir5.1 channel forms the major K+ channel in the basolateral membrane of mouse renal collecting duct principal cells. Am J Physiol Ren Physiol 294(6):F1398–F1407CrossRefGoogle Scholar
  38. 38.
    Lelievre-Pegorier M, Merlet-Benichou C, Roinel N, de Rouffignac C (1983) Developmental pattern of water and electrolyte transport in rat superficial nephrons. Am J Physiol 245(1):F15–F21PubMedGoogle Scholar
  39. 39.
    Lesage F, Guillemare E, Fink M, Duprat F, Lazdunski M, Romey G, Barhanin J (1996) TWIK-1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure. EMBO J 15(5):1004–1011PubMedGoogle Scholar
  40. 40.
    Leung YM, Zeng WZ, Liou HH, Solaro CR, Huang CL (2000) Phosphatidylinositol 4,5-bisphosphate and intracellular pH regulate the ROMK1 potassium channel via separate but interrelated mechanisms. J Biol Chem 275(14):10182–10189PubMedCrossRefGoogle Scholar
  41. 41.
    Liu Y, McKenna E, Figueroa DJ, Blevins R, Austin CP, Bennett PB, Swanson R (2000) The human inward rectifier K(+) channel subunit kir5.1 (KCNJ16) maps to chromosome 17q25 and is expressed in kidney and pancreas. Cytogenet Cell Genet 90(1–2):60–63PubMedCrossRefGoogle Scholar
  42. 42.
    Loffing J, Loffing-Cueni D, Macher A, Hebert SC, Olson B, Knepper MA, Rossier BC, Kaissling B (2000) Localization of epithelial sodium channel and aquaporin-2 in rabbit kidney cortex. Am J Physiol Ren Physiol 278(4):F530–F539Google Scholar
  43. 43.
    Loffing J, Loffing-Cueni D, Valderrabano V, Klausli L, Hebert SC, Rossier BC, Hoenderop JG, Bindels RJ, Kaissling B (2001) Distribution of transcellular calcium and sodium transport pathways along mouse distal nephron. Am J Physiol Ren Physiol 281(6):F1021–F1027Google Scholar
  44. 44.
    Loffing J, Vallon V, Loffing-Cueni D, Aregger F, Richter K, Pietri L, Bloch-Faure M, Hoenderop JG, Shull GE, Meneton P, Kaissling B (2004) Altered renal distal tubule structure and renal Na(+) and Ca(2+) handling in a mouse model for Gitelman’s syndrome. J Am Soc Nephrol 15(9):2276–2288PubMedCrossRefGoogle Scholar
  45. 45.
    Lorenz JN, Baird NR, Judd LM, Noonan WT, Andringa A, Doetschman T, Manning PA, Liu LH, Miller ML, Shull GE (2002) Impaired renal NaCl absorption in mice lacking the ROMK potassium channel, a model for type II Bartter’s syndrome. J Biol Chem 277(40):37871–37880PubMedCrossRefGoogle Scholar
  46. 46.
    Lourdel S, Paulais M, Cluzeaud F, Bens M, Tanemoto M, Kurachi Y, Vandewalle A, Teulon J (2002) An inward rectifier K(+) channel at the basolateral membrane of the mouse distal convoluted tubule: similarities with Kir4–Kir5.1 heteromeric channels. J Physiol 538(Pt 2):391–404PubMedCrossRefGoogle Scholar
  47. 47.
    Marcus DC, Wu T, Wangemann P, Kofuji P (2002) KCNJ10 (Kir4.1) potassium channel knockout abolishes endocochlear potential. Am J Physiol Cell Physiol 282(2):C403–C407PubMedGoogle Scholar
  48. 48.
    McNicholas CM, MacGregor GG, Islas LD, Yang Y, Hebert SC, Giebisch G (1998) pH-dependent modulation of the cloned renal K+ channel, ROMK. Am J Physiol 275(6 Pt 2):F972–F981PubMedGoogle Scholar
  49. 49.
    Meij IC, Koenderink JB, De Jong JC, De Pont JJ, Monnens LA, Van Den Heuvel LP, Knoers NV (2003) Dominant isolated renal magnesium loss is caused by misrouting of the Na+, K+-ATPase gamma-subunit. Ann NY Acad Sci 986:437–443PubMedCrossRefGoogle Scholar
  50. 50.
    Meij IC, Koenderink JB, van Bokhoven H, Assink KF, Groenestege WT, De Pont JJ, Bindels RJ, Monnens LA, Van Den Heuvel LP, Knoers NV (2000) Dominant isolated renal magnesium loss is caused by misrouting of the Na(+), K(+)-ATPase gamma-subunit. Nat Genet 26(3):265–266PubMedCrossRefGoogle Scholar
  51. 51.
    Murthy M, Cope G, O'Shaughnessy KM (2008) The acidic motif of WNK4 is crucial for its interaction with the K channel ROMK. Biochem Biophys Res Commun 375(4):651–654PubMedCrossRefGoogle Scholar
  52. 52.
    Nie X, Arrighi I, Kaissling B, Pfaff I, Mann J, Barhanin J, Vallon V (2005) Expression and insights on function of potassium channel TWIK-1 in mouse kidney. Pflugers Arch 451(3):479–488PubMedCrossRefGoogle Scholar
  53. 53.
    Nijenhuis T, Vallon V, van der Kemp AW, Loffing J, Hoenderop JG, Bindels RJ (2005) Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest 115(6):1651–1658PubMedCrossRefGoogle Scholar
  54. 54.
    Obermuller N, Bernstein P, Velazquez H, Reilly R, Moser D, Ellison DH, Bachmann S (1995) Expression of the thiazide-sensitive Na–Cl cotransporter in rat and human kidney. Am J Physiol 269(6 Pt 2):F900–F910PubMedGoogle Scholar
  55. 55.
    Orkand RK, Nicholls JG, Kuffler SW (1966) Effect of nerve impulses on the membrane potential of glial cells in the central nervous system of amphibia. J Neurophysiol 29(4):788–806PubMedGoogle Scholar
  56. 56.
    Paynter JJ, Shang L, Bollepalli MK, Baukrowitz T, Tucker SJ (2010) Random mutagenesis screening indicates the absence of a separate H(+)-sensor in the pH-sensitive Kir channels. Channels (Austin) 4(5):390–397Google Scholar
  57. 57.
    Pessia M, Imbrici P, D'Adamo MC, Salvatore L, Tucker SJ (2001) Differential pH sensitivity of Kir4.1 and Kir4.2 potassium channels and their modulation by heteropolymerisation with Kir5.1. J Physiol 532(Pt 2):359–367PubMedCrossRefGoogle Scholar
  58. 58.
    Pessia M, Tucker SJ, Lee K, Bond CT, Adelman JP (1996) Subunit positional effects revealed by novel heteromeric inwardly rectifying K+ channels. EMBO J 15(12):2980–2987PubMedGoogle Scholar
  59. 59.
    Rapedius M, Fowler PW, Shang L, Sansom MS, Tucker SJ, Baukrowitz T (2007) H bonding at the helix-bundle crossing controls gating in Kir potassium channels. Neuron 55(4):602–614PubMedCrossRefGoogle Scholar
  60. 60.
    Rapedius M, Haider S, Browne KF, Shang L, Sansom MS, Baukrowitz T, Tucker SJ (2006) Structural and functional analysis of the putative pH sensor in the Kir1.1 (ROMK) potassium channel. EMBO Rep 7(6):611–616PubMedGoogle Scholar
  61. 61.
    Rapedius M, Paynter JJ, Fowler PW, Shang L, Sansom MS, Tucker SJ, Baukrowitz T (2007) Control of pH and PIP2 gating in heteromeric Kir4.1/Kir5.1 channels by H-bonding at the helix-bundle crossing. Channels (Austin) 1(5):327–330Google Scholar
  62. 62.
    Reichold M, Zdebik AA, Lieberer E, Rapedius M, Schmidt K, Bandulik S, Sterner C, Tegtmeier I, Penton D, Baukrowitz T, Hulton SA, Witzgall R, Ben-Zeev B, Howie AJ, Kleta R, Bockenhauer D, Warth R (2010) KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function. Proc Natl Acad Sci USA 107(32):14490–14495PubMedCrossRefGoogle Scholar
  63. 63.
    Reilly RF, Ellison DH (2000) Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy. Physiol Rev 80(1):277–313PubMedGoogle Scholar
  64. 64.
    Rho JM, Szot P, Tempel BL, Schwartzkroin PA (1999) Developmental seizure susceptibility of kv1.1 potassium channel knockout mice. Dev Neurosci 21(3–5):320–327PubMedCrossRefGoogle Scholar
  65. 65.
    Rozengurt N, Lopez I, Chiu CS, Kofuji P, Lester HA, Neusch C (2003) Time course of inner ear degeneration and deafness in mice lacking the Kir4.1 potassium channel subunit. Hear Res 177(1–2):71–80PubMedCrossRefGoogle Scholar
  66. 66.
    Sala-Rabanal M, Kucheryavykh LY, Skatchkov SN, Eaton MJ, Nichols CG (2010) Molecular mechanisms of EAST/SeSAME syndrome mutations in Kir4.1 (KCNJ10). J Biol Chem 285(46):36040–36048PubMedCrossRefGoogle Scholar
  67. 67.
    Scheinman SJ, Guay-Woodford LM, Thakker RV, Warnock DG (1999) Genetic disorders of renal electrolyte transport. N Engl J Med 340(15):1177–1187PubMedCrossRefGoogle Scholar
  68. 68.
    Schlingmann KP, Weber S, Peters M, Niemann NL, Vitzthum H, Klingel K, Kratz M, Haddad E, Ristoff E, Dinour D, Syrrou M, Nielsen S, Sassen M, Waldegger S, Seyberth HW, Konrad M (2002) Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet 31(2):166–170PubMedCrossRefGoogle Scholar
  69. 69.
    Scholl UI, Choi M, Liu T, Ramaekers VT, Hausler MG, Grimmer J, Tobe SW, Farhi A, Nelson-Williams C, Lifton RP (2009) Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10. Proc Natl Acad Sci USA 106(14):5842–5847PubMedCrossRefGoogle Scholar
  70. 70.
    Schulte U, Hahn H, Konrad M, Jeck N, Derst C, Wild K, Weidemann S, Ruppersberg JP, Fakler B, Ludwig J (1999) pH gating of ROMK (K(ir)1.1) channels: control by an Arg-Lys-Arg triad disrupted in antenatal Bartter syndrome. Proc Natl Acad Sci USA 96(26):15298–15303PubMedCrossRefGoogle Scholar
  71. 71.
    Schultheis PJ, Lorenz JN, Meneton P, Nieman ML, Riddle TM, Flagella M, Duffy JJ, Doetschman T, Miller ML, Shull GE (1998) Phenotype resembling Gitelman’s syndrome in mice lacking the apical Na+-Cl cotransporter of the distal convoluted tubule. J Biol Chem 273(44):29150–29155PubMedCrossRefGoogle Scholar
  72. 72.
    Schulze D, Krauter T, Fritzenschaft H, Soom M, Baukrowitz T (2003) Phosphatidylinositol 4,5-bisphosphate (PIP2) modulation of ATP and pH sensitivity in Kir channels. A tale of an active and a silent PIP2 site in the N terminus. J Biol Chem 278(12):10500–10505PubMedCrossRefGoogle Scholar
  73. 73.
    Simon DB, Bindra RS, Mansfield TA, Nelson-Williams C, Mendonca E, Stone R, Schurman S, Nayir A, Alpay H, Bakkaloglu A, Rodriguez-Soriano J, Morales JM, Sanjad SA, Taylor CM, Pilz D, Brem A, Trachtman H, Griswold W, Richard GA, John E, Lifton RP (1997) Mutations in the chloride channel gene, CLCNKB, cause Bartter’s syndrome type III. Nat Genet 17(2):171–178PubMedCrossRefGoogle Scholar
  74. 74.
    Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, Vaara I, Iwata F, Cushner HM, Koolen M, Gainza FJ, Gitleman HJ, Lifton RP (1996) Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na–Cl cotransporter. Nat Genet 12(1):24–30PubMedCrossRefGoogle Scholar
  75. 75.
    Takumi T, Ishii T, Horio Y, Morishige K, Takahashi N, Yamada M, Yamashita T, Kiyama H, Sohmiya K, Nakanishi S, Kurachi Y (1995) A novel ATP-dependent inward rectifier potassium channel expressed predominantly in glial cells. J Biol Chem 270(27):16339–16346PubMedCrossRefGoogle Scholar
  76. 76.
    Tanemoto M, Abe T, Ito S (2005) PDZ-binding and di-hydrophobic motifs regulate distribution of Kir4.1 channels in renal cells. J Am Soc Nephrol 16(9):2608–2614PubMedCrossRefGoogle Scholar
  77. 77.
    Tanemoto M, Abe T, Onogawa T, Ito S (2004) PDZ binding motif-dependent localization of K+ channel on the basolateral side in distal tubules. Am J Physiol Ren Physiol 287(6):F1148–F1153CrossRefGoogle Scholar
  78. 78.
    Tanemoto M, Fujita A, Higashi K, Kurachi Y (2002) PSD-95 mediates formation of a functional homomeric Kir5.1 channel in the brain. Neuron 34(3):387–397PubMedCrossRefGoogle Scholar
  79. 79.
    Tanemoto M, Kittaka N, Inanobe A, Kurachi Y (2000) In vivo formation of a proton-sensitive K+ channel by heteromeric subunit assembly of Kir5.1 with Kir4.1. J Physiol 525 Pt 3:587–592PubMedCrossRefGoogle Scholar
  80. 80.
    Tang X, Hang D, Sand A, Kofuji P (2010) Variable loss of Kir4.1 channel function in SeSAME syndrome mutations. Biochem Biophys Res Commun 399(4):537–541PubMedCrossRefGoogle Scholar
  81. 81.
    Tucker SJ, Imbrici P, Salvatore L, D'Adamo MC, Pessia M (2000) pH dependence of the inwardly rectifying potassium channel, Kir5.1, and localization in renal tubular epithelia. J Biol Chem 275(22):16404–16407PubMedCrossRefGoogle Scholar
  82. 82.
    Vallon V, Grahammer F, Volkl H, Sandu CD, Richter K, Rexhepaj R, Gerlach U, Rong Q, Pfeifer K, Lang F (2005) KCNQ1-dependent transport in renal and gastrointestinal epithelia. Proc Natl Acad Sci USA 102(49):17864–17869PubMedCrossRefGoogle Scholar
  83. 83.
    van der Wijst J, Glaudemans B, Venselaar H, Nair AV, Forst AL, Hoenderop JG, Bindels RJ (2010) Functional analysis of the Kv1.1 N255D mutation associated with autosomal dominant hypomagnesemia. J Biol Chem 285(1):171–178PubMedCrossRefGoogle Scholar
  84. 84.
    Vargas-Poussou R, Huang C, Hulin P, Houillier P, Jeunemaitre X, Paillard M, Planelles G, Dechaux M, Miller RT, Antignac C (2002) Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome. J Am Soc Nephrol 13(9):2259–2266PubMedCrossRefGoogle Scholar
  85. 85.
    Voets T, Nilius B, Hoefs S, van der Kemp AW, Droogmans G, Bindels RJ, Hoenderop JG (2004) TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem 279(1):19–25PubMedCrossRefGoogle Scholar
  86. 86.
    Walder RY, Landau D, Meyer P, Shalev H, Tsolia M, Borochowitz Z, Boettger MB, Beck GE, Englehardt RK, Carmi R, Sheffield VC (2002) Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet 31(2):171–174PubMedCrossRefGoogle Scholar
  87. 87.
    Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, de JT S, PJ TJA, Moss AJ, Atkinson DL, Landes GM, Connors TD, Keating MT (1996) Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 12(1):17–23PubMedCrossRefGoogle Scholar
  88. 88.
    Wang WH, Lu M, Hebert SC (1996) Cytochrome P-450 metabolites mediate extracellular Ca(2+)-induced inhibition of apical K+ channels in the TAL. Am J Physiol 271(1 Pt 1):C103–C111PubMedGoogle Scholar
  89. 89.
    Watanabe S, Fukumoto S, Chang H, Takeuchi Y, Hasegawa Y, Okazaki R, Chikatsu N, Fujita T (2002) Association between activating mutations of calcium-sensing receptor and Bartter’s syndrome. Lancet 360(9334):692–694PubMedCrossRefGoogle Scholar
  90. 90.
    Williams DM, Lopes CM, Rosenhouse-Dantsker A, Connelly HL, Matavel A, Uchi J, McBeath E, Gray DA (2010) Molecular basis of decreased Kir4.1 function in SeSAME/EAST syndrome. J Am Soc Nephrol 21(12):2117–2129PubMedCrossRefGoogle Scholar
  91. 91.
    Wilson FH, Disse-Nicodeme S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP (2001) Human hypertension caused by mutations in WNK kinases. Science 293(5532):1107–1112PubMedCrossRefGoogle Scholar
  92. 92.
    Xi Q, Hoenderop JG, Bindels RJ (2009) Regulation of magnesium reabsorption in DCT. Pflugers Arch 458(1):89–98PubMedCrossRefGoogle Scholar
  93. 93.
    Xu H, Cui N, Yang Z, Qu Z, Jiang C (2000) Modulation of kir4.1 and kir5.1 by hypercapnia and intracellular acidosis. J Physiol 524 Pt 3:725–735PubMedCrossRefGoogle Scholar
  94. 94.
    Xu JZ, Hall AE, Peterson LN, Bienkowski MJ, Eessalu TE, Hebert SC (1997) Localization of the ROMK protein on apical membranes of rat kidney nephron segments. Am J Physiol 273(5 Pt 2):F739–F748PubMedGoogle Scholar
  95. 95.
    Yamauchi K, Rai T, Kobayashi K, Sohara E, Suzuki T, Itoh T, Suda S, Hayama A, Sasaki S, Uchida S (2004) Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins. Proc Natl Acad Sci USA 101(13):4690–4694PubMedCrossRefGoogle Scholar
  96. 96.
    Yang Z, Jiang C (1999) Opposite effects of pH on open-state probability and single channel conductance of kir4.1 channels. J Physiol 520 Pt 3:921–927PubMedCrossRefGoogle Scholar
  97. 97.
    Yang Z, Xu H, Cui N, Qu Z, Chanchevalap S, Shen W, Jiang C (2000) Biophysical and molecular mechanisms underlying the modulation of heteromeric Kir4.1–Kir5.1 channels by CO2 and pH. J Gen Physiol 116(1):33–45PubMedCrossRefGoogle Scholar
  98. 98.
    Zdebik AA, Wangemann P, Jentsch TJ (2009) Potassium ion movement in the inner ear: insights from genetic disease to mouse models. Physiology (Bethesda) 24:307–316Google Scholar
  99. 99.
    Zheng W, Verlander JW, Lynch IJ, Cash M, Shao J, Stow LR, Cain BD, Weiner ID, Wall SM, Wingo CS (2007) Cellular distribution of the potassium channel KCNQ1 in normal mouse kidney. Am J Physiol Ren Physiol 292(1):F456–F466CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Sascha Bandulik
    • 1
  • Katharina Schmidt
    • 1
  • Detlef Bockenhauer
    • 2
    • 4
  • Anselm A. Zdebik
    • 3
    • 4
  • Evelyn Humberg
    • 1
  • Robert Kleta
    • 2
    • 3
    • 4
  • Richard Warth
    • 1
    Email author
  • Markus Reichold
    • 1
  1. 1.Medical Cell BiologyUniversity of RegensburgRegensburgGermany
  2. 2.Great Ormond Street HospitalInstitute of Child Health, UCLLondonUK
  3. 3.Department of Neuroscience, Physiology, and Pharmacology, UCLLondonUK
  4. 4.Department of Medicine, UCLLondonUK

Personalised recommendations