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.
Alkaline pH block of CLC-Kkidney chloride channels mediated by a pore lysine residue.
Gradogna A
,
Pusch M
.
???displayArticle.abstract???
CLC-K chloride channels are expressed in the kidney and the inner ear, where they are involved in NaCl reabsorption and endolymph production, respectively. These channels require the beta subunit barttin for proper function. Mutations in ClC-Kb and barttin, lead to Bartter's syndrome. Block of CLC-K channels by acid pH was described in a previous work, and we had identified His-497 as being responsible for the acidic block of CLC-K channels. Here, we show that ClC-K currents are blocked also by alkaline pH with an apparent pK value of ∼8.7 for ClC-K1. Using noise analysis, we demonstrate that alkaline block is mediated by an allosteric reduction of the open probability. By an extensive mutagenic screen we identified K165, a highly conserved residue in the extracellular vestibule of the channel, as the major element responsible for the alkaline pH modulation. Deprotonation of K165 underlies the alkaline block. However, MTS modification of the K165C mutant demonstrated that not only the charge but also the chemical and sterical properties of lysine 165 are determinants of CLC-K gating.
Accardi,
Conformational changes in the pore of CLC-0.
2003, Pubmed,
Xenbase
Accardi,
Conformational changes in the pore of CLC-0.
2003,
Pubmed
,
Xenbase
Accardi,
Secondary active transport mediated by a prokaryotic homologue of ClC Cl- channels.
2004,
Pubmed
Accardi,
Synergism between halide binding and proton transport in a CLC-type exchanger.
2006,
Pubmed
Arreola,
Conformation-dependent regulation of inward rectifier chloride channel gating by extracellular protons.
2002,
Pubmed
Bennetts,
Inhibition of skeletal muscle ClC-1 chloride channels by low intracellular pH and ATP.
2007,
Pubmed
Birkenhäger,
Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure.
2001,
Pubmed
Chen,
Different fast-gate regulation by external Cl(-) and H(+) of the muscle-type ClC chloride channels.
2001,
Pubmed
,
Xenbase
De Stefano,
Extracellular determinants of anion discrimination of the Cl-/H+ antiporter protein CLC-5.
2011,
Pubmed
,
Xenbase
Dutzler,
Gating the selectivity filter in ClC chloride channels.
2003,
Pubmed
,
Xenbase
Dutzler,
X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity.
2002,
Pubmed
Estévez,
Barttin is a Cl- channel beta-subunit crucial for renal Cl- reabsorption and inner ear K+ secretion.
2001,
Pubmed
,
Xenbase
Fahlke,
Pore-forming segments in voltage-gated chloride channels.
1997,
Pubmed
Fischer,
Barttin activates ClC-K channel function by modulating gating.
2010,
Pubmed
Friedrich,
Mutational analysis demonstrates that ClC-4 and ClC-5 directly mediate plasma membrane currents.
1999,
Pubmed
,
Xenbase
Gradogna,
Dissecting a regulatory calcium-binding site of CLC-K kidney chloride channels.
2012,
Pubmed
Gradogna,
Molecular Pharmacology of Kidney and Inner Ear CLC-K Chloride Channels.
2010,
Pubmed
Gradogna,
A regulatory calcium-binding site at the subunit interface of CLC-K kidney chloride channels.
2010,
Pubmed
,
Xenbase
Hanke,
Single chloride channels from Torpedo electroplax. Activation by protons.
1983,
Pubmed
Heinemann,
Nonstationary noise analysis and application to patch clamp recordings.
1992,
Pubmed
Iyer,
A biological role for prokaryotic ClC chloride channels.
2002,
Pubmed
Jentsch,
CLC chloride channels and transporters.
2005,
Pubmed
Jentsch,
Chloride channel diseases resulting from impaired transepithelial transport or vesicular function.
2005,
Pubmed
Jordt,
Molecular dissection of gating in the ClC-2 chloride channel.
1997,
Pubmed
,
Xenbase
Kieferle,
Two highly homologous members of the ClC chloride channel family in both rat and human kidney.
1994,
Pubmed
Koeppen,
The kidney and acid-base regulation.
2009,
Pubmed
Liantonio,
Molecular switch for CLC-K Cl- channel block/activation: optimal pharmacophoric requirements towards high-affinity ligands.
2008,
Pubmed
,
Xenbase
Liantonio,
Investigations of pharmacologic properties of the renal CLC-K1 chloride channel co-expressed with barttin by the use of 2-(p-Chlorophenoxy)propionic acid derivatives and other structurally unrelated chloride channels blockers.
2004,
Pubmed
,
Xenbase
Liantonio,
Activation and inhibition of kidney CLC-K chloride channels by fenamates.
2006,
Pubmed
,
Xenbase
Liantonio,
Molecular requisites for drug binding to muscle CLC-1 and renal CLC-K channel revealed by the use of phenoxy-alkyl derivatives of 2-(p-chlorophenoxy)propionic acid.
2002,
Pubmed
,
Xenbase
Lin,
Probing the pore of ClC-0 by substituted cysteine accessibility method using methane thiosulfonate reagents.
2003,
Pubmed
Lin,
Cysteine modification of a putative pore residue in ClC-0: implication for the pore stoichiometry of ClC chloride channels.
2000,
Pubmed
,
Xenbase
Ludewig,
Inward rectification in ClC-0 chloride channels caused by mutations in several protein regions.
1997,
Pubmed
Mindell,
ClC chloride channels.
2001,
Pubmed
Niemeyer,
Voltage-dependent and -independent titration of specific residues accounts for complex gating of a ClC chloride channel by extracellular protons.
2009,
Pubmed
Niemeyer,
A conserved pore-lining glutamate as a voltage- and chloride-dependent gate in the ClC-2 chloride channel.
2003,
Pubmed
Picollo,
Molecular determinants of differential pore blocking of kidney CLC-K chloride channels.
2004,
Pubmed
Picollo,
Mechanism of interaction of niflumic acid with heterologously expressed kidney CLC-K chloride channels.
2007,
Pubmed
,
Xenbase
Picollo,
Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5.
2005,
Pubmed
Pusch,
Low single channel conductance of the major skeletal muscle chloride channel, ClC-1.
1994,
Pubmed
,
Xenbase
Rickheit,
Endocochlear potential depends on Cl- channels: mechanism underlying deafness in Bartter syndrome IV.
2008,
Pubmed
Rychkov,
Concentration and pH dependence of skeletal muscle chloride channel ClC-1.
1996,
Pubmed
,
Xenbase
Saviane,
The muscle chloride channel ClC-1 has a double-barreled appearance that is differentially affected in dominant and recessive myotonia.
1999,
Pubmed
,
Xenbase
Schlingmann,
Salt wasting and deafness resulting from mutations in two chloride channels.
2004,
Pubmed
,
Xenbase
Scholl,
Barttin modulates trafficking and function of ClC-K channels.
2006,
Pubmed
Simon,
Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK.
1996,
Pubmed
Simon,
Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III.
1997,
Pubmed
Simon,
Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2.
1996,
Pubmed
Sánchez-Rodríguez,
Sequential interaction of chloride and proton ions with the fast gate steer the voltage-dependent gating in ClC-2 chloride channels.
2012,
Pubmed
Traverso,
Proton sensing of CLC-0 mutant E166D.
2006,
Pubmed
,
Xenbase
Uchida,
Molecular cloning of a chloride channel that is regulated by dehydration and expressed predominantly in kidney medulla.
1993,
Pubmed
,
Xenbase
Uchida,
Localization and functional characterization of rat kidney-specific chloride channel, ClC-K1.
1995,
Pubmed
,
Xenbase
Waldegger,
Barttin increases surface expression and changes current properties of ClC-K channels.
2002,
Pubmed
,
Xenbase
Waldegger,
Functional and structural analysis of ClC-K chloride channels involved in renal disease.
2000,
Pubmed
,
Xenbase
Zdebik,
Potassium ion movement in the inner ear: insights from genetic disease and mouse models.
2009,
Pubmed
Zifarelli,
Intracellular proton regulation of ClC-0.
2008,
Pubmed
,
Xenbase
Zifarelli,
The role of protons in fast and slow gating of the Torpedo chloride channel ClC-0.
2010,
Pubmed
Zifarelli,
Identification of sites responsible for the potentiating effect of niflumic acid on ClC-Ka kidney chloride channels.
2010,
Pubmed
,
Xenbase
Zifarelli,
Conversion of the 2 Cl(-)/1 H+ antiporter ClC-5 in a NO3(-)/H+ antiporter by a single point mutation.
2009,
Pubmed
,
Xenbase
