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Molecular Pharmacology

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Research ArticleArticle

Activation and Inhibition of Kidney CLC-K Chloride Channels by Fenamates

Antonella Liantonio, Alessandra Picollo, Elena Babini, Giuseppe Carbonara, Giuseppe Fracchiolla, Fulvio Loiodice, Vincenzo Tortorella, Michael Pusch and Diana Conte Camerino
Molecular Pharmacology January 2006, 69 (1) 165-173; DOI: https://doi.org/10.1124/mol.105.017384
Antonella Liantonio
Unità di Farmacologia, Dipartimento Farmacobiologico (A.L., D.C.C.) and Dipartimento Farmacochimico (G.C., G.F., F.L., V.T.), Facoltà di Farmacia, Università di Bari, Bari, Italy; and Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Genova, Italy (A.P., E.B., M.P.)
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Alessandra Picollo
Unità di Farmacologia, Dipartimento Farmacobiologico (A.L., D.C.C.) and Dipartimento Farmacochimico (G.C., G.F., F.L., V.T.), Facoltà di Farmacia, Università di Bari, Bari, Italy; and Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Genova, Italy (A.P., E.B., M.P.)
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Elena Babini
Unità di Farmacologia, Dipartimento Farmacobiologico (A.L., D.C.C.) and Dipartimento Farmacochimico (G.C., G.F., F.L., V.T.), Facoltà di Farmacia, Università di Bari, Bari, Italy; and Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Genova, Italy (A.P., E.B., M.P.)
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Giuseppe Carbonara
Unità di Farmacologia, Dipartimento Farmacobiologico (A.L., D.C.C.) and Dipartimento Farmacochimico (G.C., G.F., F.L., V.T.), Facoltà di Farmacia, Università di Bari, Bari, Italy; and Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Genova, Italy (A.P., E.B., M.P.)
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Giuseppe Fracchiolla
Unità di Farmacologia, Dipartimento Farmacobiologico (A.L., D.C.C.) and Dipartimento Farmacochimico (G.C., G.F., F.L., V.T.), Facoltà di Farmacia, Università di Bari, Bari, Italy; and Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Genova, Italy (A.P., E.B., M.P.)
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Fulvio Loiodice
Unità di Farmacologia, Dipartimento Farmacobiologico (A.L., D.C.C.) and Dipartimento Farmacochimico (G.C., G.F., F.L., V.T.), Facoltà di Farmacia, Università di Bari, Bari, Italy; and Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Genova, Italy (A.P., E.B., M.P.)
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Vincenzo Tortorella
Unità di Farmacologia, Dipartimento Farmacobiologico (A.L., D.C.C.) and Dipartimento Farmacochimico (G.C., G.F., F.L., V.T.), Facoltà di Farmacia, Università di Bari, Bari, Italy; and Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Genova, Italy (A.P., E.B., M.P.)
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Michael Pusch
Unità di Farmacologia, Dipartimento Farmacobiologico (A.L., D.C.C.) and Dipartimento Farmacochimico (G.C., G.F., F.L., V.T.), Facoltà di Farmacia, Università di Bari, Bari, Italy; and Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Genova, Italy (A.P., E.B., M.P.)
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Diana Conte Camerino
Unità di Farmacologia, Dipartimento Farmacobiologico (A.L., D.C.C.) and Dipartimento Farmacochimico (G.C., G.F., F.L., V.T.), Facoltà di Farmacia, Università di Bari, Bari, Italy; and Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Genova, Italy (A.P., E.B., M.P.)
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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 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, 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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Molecular Pharmacology: 69 (1)
Molecular Pharmacology
Vol. 69, Issue 1
1 Jan 2006
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Research ArticleArticle

Activation and Inhibition of Kidney CLC-K Chloride Channels by Fenamates

Antonella Liantonio, Alessandra Picollo, Elena Babini, Giuseppe Carbonara, Giuseppe Fracchiolla, Fulvio Loiodice, Vincenzo Tortorella, Michael Pusch and Diana Conte Camerino
Molecular Pharmacology January 1, 2006, 69 (1) 165-173; DOI: https://doi.org/10.1124/mol.105.017384

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Research ArticleArticle

Activation and Inhibition of Kidney CLC-K Chloride Channels by Fenamates

Antonella Liantonio, Alessandra Picollo, Elena Babini, Giuseppe Carbonara, Giuseppe Fracchiolla, Fulvio Loiodice, Vincenzo Tortorella, Michael Pusch and Diana Conte Camerino
Molecular Pharmacology January 1, 2006, 69 (1) 165-173; DOI: https://doi.org/10.1124/mol.105.017384
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