Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Am Soc Nephrol
2010 Dec 01;2112:2117-29. doi: 10.1681/ASN.2009121227.
Show Gene links
Show Anatomy links
Molecular basis of decreased Kir4.1 function in SeSAME/EAST syndrome.
Williams DM
,
Lopes CM
,
Rosenhouse-Dantsker A
,
Connelly HL
,
Matavel A
,
O-Uchi J
,
McBeath E
,
Gray DA
.
???displayArticle.abstract???
SeSAME/EAST syndrome is a channelopathy consisting of a hypokalemic, hypomagnesemic, metabolic alkalosis associated with seizures, sensorineural deafness, ataxia, and developmental abnormalities. This disease links to autosomal recessive mutations in KCNJ10, which encodes the Kir4.1 potassium channel, but the functional consequences of these mutations are not well understood. In Xenopus oocytes, all of the disease-associated mutant channels (R65P, R65P/R199X, G77R, C140R, T164I, and A167V/R297C) had decreased K(+) current (0 to 23% of wild-type levels). Immunofluorescence demonstrated decreased surface expression of G77R, C140R, and A167V expressed in HEK293 cells. When we coexpressed mutant and wild-type subunits to mimic the heterozygous state, R199X, C140R, and G77R currents decreased to 55, 40, and 20% of wild-type levels, respectively, suggesting that carriers of these mutations may present with an abnormal phenotype. Because Kir4.1 subunits can form heteromeric channels with Kir5.1, we coexpressed the aforementioned mutants with Kir5.1 and found that currents were reduced at least as much as observed when we expressed mutants alone. Reduction of pH(i) from approximately 7.4 to 6.8 significantly decreased currents of all mutants except R199X but did not affect wild-type channels. In conclusion, perturbed pH gating may underlie the loss of channel function for the disease-associated mutant Kir4.1 channels and may have important physiologic consequences.
Armstrong,
Access resistance and space clamp problems associated with whole-cell patch clamping.
1992, Pubmed
Armstrong,
Access resistance and space clamp problems associated with whole-cell patch clamping.
1992,
Pubmed
Bidet,
Effect of calcitonin on the regulation of intracellular pH in primary cultures of rabbit early distal tubule.
1992,
Pubmed
Bockenhauer,
Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations.
2009,
Pubmed
,
Xenbase
Cho,
Two critical cysteine residues implicated in disulfide bond formation and proper folding of Kir2.1.
2000,
Pubmed
,
Xenbase
Choe,
A conserved cytoplasmic region of ROMK modulates pH sensitivity, conductance, and gating.
1997,
Pubmed
,
Xenbase
Dagher,
Calcitonin activates an Na(+)-independent HCO3(-)-dependent pathway in the rabbit distal convoluted tubule.
1997,
Pubmed
Djukic,
Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation.
2007,
Pubmed
Gibor,
An inactivation gate in the selectivity filter of KCNQ1 potassium channels.
2007,
Pubmed
,
Xenbase
Gitelman,
A new familial disorder characterized by hypokalemia and hypomagnesemia.
1966,
Pubmed
Glaudemans,
New molecular players facilitating Mg(2+) reabsorption in the distal convoluted tubule.
2010,
Pubmed
Gray,
Basolateral K+ conductance in principal cells of rat CCD.
2005,
Pubmed
,
Xenbase
Hibino,
Differential assembly of inwardly rectifying K+ channel subunits, Kir4.1 and Kir5.1, in brain astrocytes.
2004,
Pubmed
Hibino,
Expression of an inwardly rectifying K+ channel, Kir5.1, in specific types of fibrocytes in the cochlear lateral wall suggests its functional importance in the establishment of endocochlear potential.
2004,
Pubmed
Higashi,
An inwardly rectifying K(+) channel, Kir4.1, expressed in astrocytes surrounds synapses and blood vessels in brain.
2001,
Pubmed
Hoover,
N-Glycosylation at two sites critically alters thiazide binding and activity of the rat thiazide-sensitive Na(+):Cl(-) cotransporter.
2003,
Pubmed
,
Xenbase
Ishii,
Differential expression and distribution of Kir5.1 and Kir4.1 inwardly rectifying K+ channels in retina.
2003,
Pubmed
Ito,
Immunolocalization of an inwardly rectifying K+ channel, K(AB)-2 (Kir4.1), in the basolateral membrane of renal distal tubular epithelia.
1996,
Pubmed
Ji,
Rare independent mutations in renal salt handling genes contribute to blood pressure variation.
2008,
Pubmed
Kofuji,
Genetic inactivation of an inwardly rectifying potassium channel (Kir4.1 subunit) in mice: phenotypic impact in retina.
2000,
Pubmed
Kucheryavykh,
Downregulation of Kir4.1 inward rectifying potassium channel subunits by RNAi impairs potassium transfer and glutamate uptake by cultured cortical astrocytes.
2007,
Pubmed
Lachheb,
Kir4.1/Kir5.1 channel forms the major K+ channel in the basolateral membrane of mouse renal collecting duct principal cells.
2008,
Pubmed
Liman,
Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs.
1992,
Pubmed
,
Xenbase
Lopes,
Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies.
2002,
Pubmed
,
Xenbase
Lourdel,
An inward rectifier K(+) channel at the basolateral membrane of the mouse distal convoluted tubule: similarities with Kir4-Kir5.1 heteromeric channels.
2002,
Pubmed
Marcus,
KCNJ10 (Kir4.1) potassium channel knockout abolishes endocochlear potential.
2002,
Pubmed
Nagel,
CFTR, investigated with the two-electrode voltage-clamp technique: the importance of knowing the series resistance.
2004,
Pubmed
Neusch,
Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination.
2001,
Pubmed
Nichols,
Inward rectifier potassium channels.
1997,
Pubmed
Nishida,
Crystal structure of a Kir3.1-prokaryotic Kir channel chimera.
2007,
Pubmed
ORLOFF,
The effect of potassium in nephrectomized rats with hypokalemic alkalosis.
1953,
Pubmed
Pessia,
Subunit positional effects revealed by novel heteromeric inwardly rectifying K+ channels.
1996,
Pubmed
,
Xenbase
Pessia,
Differential pH sensitivity of Kir4.1 and Kir4.2 potassium channels and their modulation by heteropolymerisation with Kir5.1.
2001,
Pubmed
,
Xenbase
Rapedius,
Structural and functional analysis of the putative pH sensor in the Kir1.1 (ROMK) potassium channel.
2006,
Pubmed
,
Xenbase
Rapedius,
Control of pH and PIP2 gating in heteromeric Kir4.1/Kir5.1 channels by H-Bonding at the helix-bundle crossing.
2007,
Pubmed
Rapedius,
H bonding at the helix-bundle crossing controls gating in Kir potassium channels.
2007,
Pubmed
,
Xenbase
Reichold,
KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function.
2010,
Pubmed
Reilly,
Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy.
2000,
Pubmed
Reimann,
Inwardly rectifying potassium channels.
1999,
Pubmed
Rozengurt,
Time course of inner ear degeneration and deafness in mice lacking the Kir4.1 potassium channel subunit.
2003,
Pubmed
Scholl,
Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10.
2009,
Pubmed
Schulte,
pH gating of ROMK (K(ir)1.1) channels: control by an Arg-Lys-Arg triad disrupted in antenatal Bartter syndrome.
1999,
Pubmed
Schulte,
pH-dependent gating of ROMK (Kir1.1) channels involves conformational changes in both N and C termini.
1998,
Pubmed
,
Xenbase
Shyng,
Structural determinants of PIP(2) regulation of inward rectifier K(ATP) channels.
2000,
Pubmed
Tanemoto,
PSD-95 mediates formation of a functional homomeric Kir5.1 channel in the brain.
2002,
Pubmed
Tanemoto,
PDZ-binding and di-hydrophobic motifs regulate distribution of Kir4.1 channels in renal cells.
2005,
Pubmed
Tanemoto,
In vivo formation of a proton-sensitive K+ channel by heteromeric subunit assembly of Kir5.1 with Kir4.1.
2000,
Pubmed
Tanemoto,
PDZ binding motif-dependent localization of K+ channel on the basolateral side in distal tubules.
2004,
Pubmed
Tang,
Variable loss of Kir4.1 channel function in SeSAME syndrome mutations.
2010,
Pubmed
Tucker,
pH dependence of the inwardly rectifying potassium channel, Kir5.1, and localization in renal tubular epithelia.
2000,
Pubmed
Weber,
Genetic mechanisms in idiopathic epilepsies.
2008,
Pubmed
Wu,
Contribution of Kir4.1 to the mouse electroretinogram.
2004,
Pubmed
Yang,
Opposite effects of pH on open-state probability and single channel conductance of kir4.1 channels.
1999,
Pubmed
,
Xenbase
Yang,
Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome.
2009,
Pubmed
,
Xenbase
Zhang,
Carboxy-terminal determinants of conductance in inward-rectifier K channels.
2004,
Pubmed
,
Xenbase
