Mechanism of interaction of niflumic acid with heterologously expressed kidney CLC-K chloride channels

J Membr Biol. 2007 Apr;216(2-3):73-82. doi: 10.1007/s00232-007-9034-z. Epub 2007 Jul 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chloride Channels / drug effects*
  • Drug Synergism
  • Flufenamic Acid / pharmacology
  • Humans
  • Kidney / drug effects
  • Kidney / physiology*
  • Models, Biological
  • Niflumic Acid / pharmacology*
  • Phenylpropionates / pharmacology
  • Rats
  • Xenopus laevis


  • 2-(4-chlorophenoxy)-3-phenylpropanoic acid
  • CLCNKA protein, human
  • Chloride Channels
  • Clcnka protein, rat
  • Phenylpropionates
  • Niflumic Acid
  • Flufenamic Acid