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XB-ART-36992
J Membr Biol 2007 Apr 01;2162-3:73-82. doi: 10.1007/s00232-007-9034-z.
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Mechanism of interaction of niflumic acid with heterologously expressed kidney CLC-K chloride channels.

Picollo A , Liantonio A , Babini E , Camerino DC , Pusch M .


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.

PubMed ID: 17659402
Article link: J Membr Biol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: bsnd clcnkb

References [+] :
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