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

Abstract
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.
AuthorsAntonella Liantonio, Alessandra Picollo, Elena Babini, Giuseppe Carbonara, Giuseppe Fracchiolla, Fulvio Loiodice, Vincenzo Tortorella, Michael Pusch, Diana Conte Camerino
JournalMolecular pharmacology (Mol Pharmacol) Vol. 69 Issue 1 Pg. 165-73 (Jan 2006) ISSN: 0026-895X [Print] United States
PMID16244177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • CLCNKA protein, human
  • Chloride Channel Agonists
  • Chloride Channels
  • ortho-Aminobenzoates
  • fenamic acid
Topics
  • Animals
  • Bartter Syndrome (drug therapy)
  • Chloride Channel Agonists
  • Chloride Channels (antagonists & inhibitors)
  • Kidney (drug effects, metabolism)
  • Xenopus laevis
  • ortho-Aminobenzoates (pharmacology, therapeutic use)

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