Mutations in the ROMK Gene in Antenatal Bartter Syndrome Are Associated with Impaired K+Channel Function

Derst, Christian; Konrad, Martin; Köckerling, Arnold; Károlyi, Lothar; Deschenes, Georges; Daut, Jürgen; Karschin, Andreas; Seyberth, Hannsjörg W.

doi:10.1006/bbrc.1996.6024

Cited by 93 publications

(55 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, although the RGD sequence is preserved in GIRK channels, it diverges slightly in other inward rectifiers, often forming an HGD motif, but the aspartate residue of the motif is well conserved throughout the family of inward rectifiers. The residue is clearly important in Kir1.1 (ROMK1), for instance, because an aspartate-to-histidine mutation produces a nonfunctional channel in one allele of Bartter syndrome (36). This conservation is consistent with the idea that other inward FIG.…”

Section: Direct Binding Of Girk To Integrin Is Required For Girksupporting

confidence: 72%

Evidence for a Functional Interaction between Integrins and G Protein-activated Inward Rectifier K+ Channels

McPhee

Dang

Davidson

et al. 1998

Journal of Biological Chemistry

View full text Add to dashboard Cite

Heteromultimeric G protein-activated inward rectifier K ؉ (GIRK) channels, abundant in heart and brain, help to determine the cellular membrane potential as well as the frequency and duration of electrical impulses. The sequence arginine-glycine-aspartate (RGD), located extracellularly between the first membranespanning region and the pore, is conserved among all identified GIRK subunits but is not found in the extracellular domain of any other cloned K ؉ channels. Many integrins, which, like channels, are integral membrane proteins, recognize this RGD sequence on other proteins, usually in the extracellular matrix. We therefore asked whether GIRK activity might be regulated by direct interaction with integrin. Here, we present evidence that mutation of the RGD site to RGE, particularly on the GIRK4 subunit, decreases or abolishes GIRK current. Furthermore, wild-type channels can be co-immunoprecipitated with integrin. The total cellular amount of expressed mutant GIRK channel protein is the same as the wild-type protein; however, the amount of mutant channel protein that localizes to the plasma membrane is decreased relative to wild-type, most likely accounting for the diminished GIRK current detected. GIRK channels appear to bind directly to integrin and to require this interaction for proper GIRK channel membrane localization and function.

show abstract

Section: Direct Binding Of Girk To Integrin Is Required For Girksupporting

confidence: 72%

Evidence for a Functional Interaction between Integrins and G Protein-activated Inward Rectifier K+ Channels

McPhee

Dang

Davidson

et al. 1998

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Type I is due to inactivating mutations in BSC1/NKCC2 (35,224,318,375,408) because absence of a functional Na ϩ -K ϩ -2Cl Ϫ cotransporter in apical membrane prevents salt transport in the TALH. Bartter syndrome type II is due to inactivating mutations in ROMK (83,207,376,419). When apical K ϩ channels are not functional, absence of K ϩ recycling quickly depletes the luminal fluid of K ϩ ; hence, Na ϩ -K ϩ -2Cl Ϫ cotransporter activity is prevented.…”

Section: B Bartter's Diseasementioning

confidence: 99%

Molecular Physiology and Pathophysiology of Electroneutral Cation-Chloride Cotransporters

Gamba

2005

Physiological Reviews

705

754

View full text Add to dashboard Cite

Electroneutral cation-Cl−cotransporters compose a family of solute carriers in which cation (Na+or K+) movement through the plasma membrane is always accompanied by Cl−in a 1:1 stoichiometry. Seven well-characterized members include one gene encoding the thiazide-sensitive Na+−Cl−cotransporter, two genes encoding loop diuretic-sensitive Na+−K+−2Cl−cotransporters, and four genes encoding K+−Cl−cotransporters. These membrane proteins are involved in several physiological activities including transepithelial ion absorption and secretion, cell volume regulation, and setting intracellular Cl−concentration below or above its electrochemical potential equilibrium. In addition, members of this family play an important role in cardiovascular and neuronal pharmacology and pathophysiology. Some of these cotransporters serve as targets for loop diuretics and thiazide-type diuretics, which are among the most commonly prescribed drugs in the world, and inactivating mutations of three members of the family cause inherited diseases such as Bartter's, Gitelman's, and Anderman's diseases. Major advances have been made in the past decade as consequences of molecular identification of all members in this family. This work is a comprehensive review of the knowledge that has evolved in this area and includes molecular biology of each gene, functional properties of identified cotransporters, structure-function relationships, and physiological and pathophysiological roles of each cotransporter.

show abstract

“…Characteristically, both renal and systemic formation of prostaglandine E 2 are markedly stimulated, resulting in further aggravation of saluretic polyuria, secretory diarrhea, and failure to thrive (25). Analysis of the ROMK gene in individual aBS patients identified a number of point mutations in the core region as well as in the intracellular N and C termini (22,24,26,27). Some of these mutations recently were shown to result in a loss of K ir 1.1 channel function in heterologous expression experiments, although the mechanisms leading to nonfunctional channels are largely unknown (27,28).…”

mentioning

confidence: 99%

“…Analysis of the ROMK gene in individual aBS patients identified a number of point mutations in the core region as well as in the intracellular N and C termini (22,24,26,27). Some of these mutations recently were shown to result in a loss of K ir 1.1 channel function in heterologous expression experiments, although the mechanisms leading to nonfunctional channels are largely unknown (27,28). A loss of ROMK function will result in impaired renal K ϩ secretion and NaCl reabsorption and lead to the clinical phenotype of aBS.…”

mentioning

confidence: 99%

pH gating of ROMK (K _ir 1.1) channels: Control by an Arg-Lys-Arg triad disrupted in antenatal Bartter syndrome

Schulte

Hahn²,

Konrad³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

139

169

View full text Add to dashboard Cite

Inward-rectifier K ؉ channels of the ROMK (Kir1.1) subtype are responsible for K ؉ secretion and control of NaCl absorption in the kidney. A hallmark of these channels is their gating by intracellular pH in the neutral range. Here we show that a lysine residue close to TM1, identified previously as a structural element required for pH-induced gating, is protonated at neutral pH and that this protonation drives pH gating in ROMK and other K ir channels. Such anomalous titration of this lysine residue (Lys-80 in K ir1.1) is accomplished by the tertiary structure of the Kir protein: two arginines in the distant N and C termini of the same subunit (Arg-41 and Arg-311 in K ir1.1) are located in close spatial proximity to the lysine allowing for electrostatic interactions that shift its pK a into the neutral pH range. Structural disturbance of this triad as a result from a number of point mutations found in patients with antenatal Bartter syndrome shifts the pK a of the lysine residue off the neutral pH range and results in channels permanently inactivated under physiological conditions. Thus, the results provide molecular understanding for normal pH gating of K ir channels as well as for the channel defects found in patients with antenatal Bartter syndrome.

show abstract

Mutations in the ROMK Gene in Antenatal Bartter Syndrome Are Associated with Impaired K+Channel Function

Cited by 93 publications

References 15 publications

Evidence for a Functional Interaction between Integrins and G Protein-activated Inward Rectifier K+ Channels

Evidence for a Functional Interaction between Integrins and G Protein-activated Inward Rectifier K+ Channels

Molecular Physiology and Pathophysiology of Electroneutral Cation-Chloride Cotransporters

pH gating of ROMK (K _ir 1.1) channels: Control by an Arg-Lys-Arg triad disrupted in antenatal Bartter syndrome

Contact Info

Product

Resources

About

Mutations in the ROMK Gene in Antenatal Bartter Syndrome Are Associated with Impaired K+Channel Function

Cited by 93 publications

References 15 publications

Evidence for a Functional Interaction between Integrins and G Protein-activated Inward Rectifier K+ Channels

Evidence for a Functional Interaction between Integrins and G Protein-activated Inward Rectifier K+ Channels

Molecular Physiology and Pathophysiology of Electroneutral Cation-Chloride Cotransporters

pH gating of ROMK (K ir 1.1) channels: Control by an Arg-Lys-Arg triad disrupted in antenatal Bartter syndrome

Contact Info

Product

Resources

About

pH gating of ROMK (K _ir 1.1) channels: Control by an Arg-Lys-Arg triad disrupted in antenatal Bartter syndrome