Activation and inhibition of kidney CLC-K chloride channels by fenamates

Mol Pharmacol. 2006 Jan;69(1):165-73. doi: 10.1124/mol.105.017384. Epub 2005 Oct 21.


CLC-K Cl(-) channels are selectively expressed in kidney and ear, where they are pivotal for salt homeostasis, and loss-of-function mutations of CLC-Kb produce Bartter's syndrome type III. The only ligand known for CLC-K channels is a derivative of the 2-p-chlorophenoxypropionic acid (CPP), 3-phenyl-CPP, which blocks CLC-Ka, but not CLC-Kb. Here we show that in addition to this blocking site, CLC-K channels bear an activating binding site that controls channel opening. Using the voltage-clamp technique on channels expressed in Xenopus laevis oocytes, we found that niflumic acid (NFA) increases CLC-Ka and CLC-Kb currents in the 10 to 1000 microM range. Flufenamic acid (FFA) derivatives or high doses of NFA produced instead an inhibitory effect on CLC-Ka, but not on CLC-Kb, and on blocker-insensitive CLC-Ka mutants, indicating that the activating binding site is distinct from the blocker site. Evaluation of the sensitivity of CLC-Ka to derivatives of NFA and FFA together with a modeling study of these ligands allow us to conclude that one major characteristic of activating compounds is the coplanarity of the two rings of the molecules, whereas block requires a noncoplanar configuration. These molecules provide a starting point for identification of diuretics or drugs useful in the treatment of Bartter's syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bartter Syndrome / drug therapy
  • Chloride Channel Agonists*
  • Chloride Channels / antagonists & inhibitors*
  • Kidney / drug effects*
  • Kidney / metabolism
  • Xenopus laevis
  • ortho-Aminobenzoates / pharmacology*
  • ortho-Aminobenzoates / therapeutic use


  • CLCNKA protein, human
  • Chloride Channel Agonists
  • Chloride Channels
  • ortho-Aminobenzoates
  • fenamic acid