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First published on October 21, 2005; DOI: 10.1124/mol.105.017384

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Received for publication July 29, 2005.
Revised October 14, 2005.
Accepted for publication October 20, 2005.

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

Antonella Liantonio 1, Alessandra Picollo 2, Elena Babini 2, Giuseppe Carbonara 3, Giuseppe Fracchiolla 3, Fulvio Loiodice 3, Vincenzo Tortorella 3, Michael Pusch 2, Diana Conte Camerino 4*

1 Section of Pharmacology,University of Bari-Italy 2 Institute of Biophysic, CNR of Genova-Italy 3 Dept. of Medicinal Chemistry, University of Bari- Italy 4 University of Bari

* Address correspondence to: E-mail: conte{at}farmbiol.uniba.it

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 controlling channel opening. Using voltage-clamp technique on channels expressed in Xenopus oocytes, we find that niflumic acid (NFA) increases CLC-Ka and CLC-Kb currents in the 10-1000 µM 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, while block requires a non-coplanar configuration. These molecules provide a starting point for identification of diuretics or drugs useful in the treatment of Bartter's syndrome.


Key words: Chloride, Structure-activity relationships and modeling, Func. analysis receptor/ion channel mutants, Mutagenesis/Chimeric approaches


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