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.
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Authors | Antonella Liantonio, Alessandra Picollo, Elena Babini, Giuseppe Carbonara, Giuseppe Fracchiolla, Fulvio Loiodice, Vincenzo Tortorella, Michael Pusch, Diana Conte Camerino |
Journal | Molecular pharmacology
(Mol Pharmacol)
Vol. 69
Issue 1
Pg. 165-73
(Jan 2006)
ISSN: 0026-895X [Print] United States |
PMID | 16244177
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- CLCNKA protein, human
- Chloride Channel Agonists
- Chloride Channels
- ortho-Aminobenzoates
- fenamic acid
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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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