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.
Br J Pharmacol
2010 Aug 01;1607:1652-61. doi: 10.1111/j.1476-5381.2010.00822.x.
Show Gene links
Show Anatomy links
Identification of sites responsible for the potentiating effect of niflumic acid on ClC-Ka kidney chloride channels.
Zifarelli G
,
Liantonio A
,
Gradogna A
,
Picollo A
,
Gramegna G
,
De Bellis M
,
Murgia AR
,
Babini E
,
Camerino DC
,
Pusch M
.
???displayArticle.abstract???
ClC-K kidney Cl(-) channels are important for renal and inner ear transepithelial Cl(-) transport, and are potentially interesting pharmacological targets. They are modulated by niflumic acid (NFA), a non-steroidal anti-inflammatory drug, in a biphasic way: NFA activates ClC-Ka at low concentrations, but blocks the channel above approximately 1 mM. We attempted to identify the amino acids involved in the activation of ClC-Ka by NFA. We used site-directed mutagenesis and two-electrode voltage clamp analysis of wild-type and mutant channels expressed in Xenopus oocytes. Guided by the crystal structure of a bacterial CLC homolog, we screened 97 ClC-Ka mutations for alterations of NFA effects. Mutations of five residues significantly reduced the potentiating effect of NFA. Two of these (G167A and F213A) drastically altered general gating properties and are unlikely to be involved in NFA binding. The three remaining mutants (L155A, G345S and A349E) severely impaired or abolished NFA potentiation. The three key residues identified (L155, G345, A349) are localized in two different protein regions that, based on the crystal structure of bacterial CLC homologs, are expected to be exposed to the extracellular side of the channel, relatively close to each other, and are thus good candidates for being part of the potentiating NFA binding site. Alternatively, the protein region identified mediates conformational changes following NFA binding. Our results are an important step towards the development of ClC-Ka activators for treating Bartter syndrome types III and IV with residual channel activity.
Abitbol,
Stilbenes and fenamates rescue the loss of I(KS) channel function induced by an LQT5 mutation and other IsK mutants.
1999, Pubmed,
Xenbase
Abitbol,
Stilbenes and fenamates rescue the loss of I(KS) channel function induced by an LQT5 mutation and other IsK mutants.
1999,
Pubmed
,
Xenbase
Accardi,
Conformational changes in the pore of CLC-0.
2003,
Pubmed
,
Xenbase
Adachi,
Two isoforms of a chloride channel predominantly expressed in thick ascending limb of Henle's loop and collecting ducts of rat kidney.
1994,
Pubmed
,
Xenbase
Akizuki,
Impaired solute accumulation in inner medulla of Clcnk1-/- mice kidney.
2001,
Pubmed
Alexander,
Guide to Receptors and Channels (GRAC), 3rd edition.
2008,
Pubmed
Birkenhäger,
Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure.
2001,
Pubmed
Busch,
Positive regulation by chloride channel blockers of IsK channels expressed in Xenopus oocytes.
1994,
Pubmed
,
Xenbase
Cheng,
Niflumic acid alters gating of HCN2 pacemaker channels by interaction with the outer region of S4 voltage sensing domains.
2009,
Pubmed
,
Xenbase
Coyne,
Characterization of the interaction between fenamates and hippocampal neuron GABA(A) receptors.
2007,
Pubmed
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,
Conservation of chloride channel structure revealed by an inhibitor binding site in ClC-1.
2003,
Pubmed
,
Xenbase
Estévez,
Barttin is a Cl- channel beta-subunit crucial for renal Cl- reabsorption and inner ear K+ secretion.
2001,
Pubmed
,
Xenbase
Fernandez,
Structural basis for ether-a-go-go-related gene K+ channel subtype-dependent activation by niflumic acid.
2008,
Pubmed
,
Xenbase
Fong,
CLC-K channels: if the drug fits, use it.
2004,
Pubmed
Foster,
Flufenamic acid is a tool for investigating TRPC6-mediated calcium signalling in human conditionally immortalised podocytes and HEK293 cells.
2009,
Pubmed
Greenwood,
Overlapping pharmacology of Ca2+-activated Cl- and K+ channels.
2007,
Pubmed
Jeck,
Activating mutation of the renal epithelial chloride channel ClC-Kb predisposing to hypertension.
2004,
Pubmed
,
Xenbase
Jentsch,
Chloride transport in the kidney: lessons from human disease and knockout mice.
2005,
Pubmed
Kieferle,
Two highly homologous members of the ClC chloride channel family in both rat and human kidney.
1994,
Pubmed
Kokubo,
Association analysis between hypertension and CYBA, CLCNKB, and KCNMB1 functional polymorphisms in the Japanese population--the Suita Study.
2005,
Pubmed
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,
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
Liantonio,
Niflumic acid inhibits chloride conductance of rat skeletal muscle by directly inhibiting the CLC-1 channel and by increasing intracellular calcium.
2007,
Pubmed
,
Xenbase
Liantonio,
Activation and inhibition of kidney CLC-K chloride channels by fenamates.
2006,
Pubmed
,
Xenbase
Liantonio,
Molecular switch for CLC-K Cl- channel block/activation: optimal pharmacophoric requirements towards high-affinity ligands.
2008,
Pubmed
,
Xenbase
Lorenz,
Heteromultimeric CLC chloride channels with novel properties.
1996,
Pubmed
,
Xenbase
Malykhina,
Fenamate-induced enhancement of heterologously expressed HERG currents in Xenopus oocytes.
2002,
Pubmed
,
Xenbase
Matsumura,
Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel.
1999,
Pubmed
Matulef,
Discovery of potent CLC chloride channel inhibitors.
2008,
Pubmed
Picollo,
Mechanism of interaction of niflumic acid with heterologously expressed kidney CLC-K chloride channels.
2007,
Pubmed
,
Xenbase
Picollo,
Molecular determinants of differential pore blocking of kidney CLC-K chloride channels.
2004,
Pubmed
Pusch,
Low single channel conductance of the major skeletal muscle chloride channel, ClC-1.
1994,
Pubmed
,
Xenbase
Pusch,
Pharmacological characterization of chloride channels belonging to the ClC family by the use of chiral clofibric acid derivatives.
2000,
Pubmed
,
Xenbase
Qu,
Functional geometry of the permeation pathway of Ca2+-activated Cl-channels inferred from analysis of voltage-dependent block.
2001,
Pubmed
,
Xenbase
Rickheit,
Endocochlear potential depends on Cl- channels: mechanism underlying deafness in Bartter syndrome IV.
2008,
Pubmed
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
Sigworth,
The variance of sodium current fluctuations at the node of Ranvier.
1980,
Pubmed
Simon,
Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III.
1997,
Pubmed
Speirs,
No association with hypertension of CLCNKB and TNFRSF1B polymorphisms at a hypertension locus on chromosome 1p36.
2005,
Pubmed
Uchida,
Function of chloride channels in the kidney.
2005,
Pubmed
Uchida,
Molecular cloning of a chloride channel that is regulated by dehydration and expressed predominantly in kidney medulla.
1993,
Pubmed
,
Xenbase
Verkman,
Chloride channels as drug targets.
2009,
Pubmed
Waldegger,
Barttin increases surface expression and changes current properties of ClC-K channels.
2002,
Pubmed
,
Xenbase
Zifarelli,
CLC chloride channels and transporters: a biophysical and physiological perspective.
2007,
Pubmed
