Mechanism of interaction of niflumic acid with heterologously expressed kidney CLC-K chloride channels.
J Membr Biol
; 216(2-3): 73-82, 2007 Apr.
Article
em En
| MEDLINE
| ID: mdl-17659402
ABSTRACT
CLC-K Cl(-) channels belong to the CLC protein family. In kidney and inner ear, they are involved in transepithelial salt transport. Mutations in ClC-Kb lead to Bartter's syndrome, and mutations in the associated subunit barttin produce Bartter's syndrome and deafness. We have previously found that 3-phenyl-CPP blocks hClC-Ka and rClC-K1 from the extracellular side in the pore entrance. Recently, we have shown that niflumic acid (NFA), a nonsteroidal anti-inflammatory fenamate, produces biphasic behavior on human CLC-K channels that suggests the presence of two functionally different binding sites an activating site and a blocking site. Here, we investigate in more detail the interaction of NFA on CLC-K channels. Mutants that altered block by 3-phenyl-2-(p-chlorophenoxy)propionic acid (CPP) had no effect on NFA block, indicating that the inhibition binding site of NFA is different from that of 3-phenyl-CPP and flufenamic acid. Moreover, NFA does not compete with extracellular Cl(-) ions, suggesting that the binding sites of NFA are not located deep in the pore. Differently from ClC-Ka, on the rat homologue ClC-K1, NFA has only an inhibitory effect. We developed a quantitative model to describe the complex action of NFA on ClC-Ka. The model predicts that ClC-Ka possesses two NFA binding sites when only one site is occupied, NFA increases ClC-Ka currents, whereas the occupation of both binding sites leads to channel block.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácido Niflúmico
/
Canais de Cloreto
/
Rim
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Membr Biol
Ano de publicação:
2007
Tipo de documento:
Article