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Originally published In Press as doi:10.1074/jbc.M206121200 on July 17, 2002

J. Biol. Chem., Vol. 277, Issue 39, 35999-36004, September 27, 2002
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The Cystic Fibrosis Mutation G551D Alters the Non-Michaelis-Menten Behavior of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channel and Abolishes the Inhibitory Genistein Binding Site*

Renaud Dérand, Laurence Bulteau-Pignoux, and Frédéric BecqDagger

From the From LBSC, CNRS UMR 6558, Université de Poitiers, 40 Avenue du Recteur Pineau, 86022 Poitiers, France

Loss of cystic fibrosis transmembrane conductance regulator (CFTR) channel activity explains most of the manifestations of the cystic fibrosis (CF) disease. To understand the consequences of CF mutations on CFTR channel activity, we compared the pharmacological properties of wild-type (wt) and G551D-CFTR. Dose-dependent relationships of wt-CFTR activated by genistein follows a non-Michaelis-Menten behavior consistent with the presence of two binding sites. With phosphorylated CFTR, a high affinity site for genistein is the activator (Ks approx  3 µM), whereas a second site of low affinity (Ki approx  75 µM) is the inhibitor. With non-phosphorylated CFTR, Ks was increased (Ks approx  12 µM), but Ki was not affected (Ki approx  70 µM). In G551D-CFTR cells, channel activity was recovered by co-application of forskolin and genistein in a dose-dependent manner. A further stimulation of G551D-CFTR channel activity was measured at concentrations from 30 µM to 1 mM. The dose response is described by a classical Michaelis-Menten kinetics with only a single apparent site (Km approx  11 µM). Our results suggest glycine 551 in NBD1 as an important location within the low affinity inhibitory site for genistein and offers new evidence for pharmacological alteration caused by an NBD1 mutation of CFTR. This study also reveals how a mutation of an ion channel converts a non-Michaelis-Menten behavior (two binding sites) into a classical Michaelis-Menten model (one binding site).

* This work was supported by Vaincre La Mucoviscidose.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed. Tel.: 33-549-45-37-29; Fax: 33-549-45-40-14; E-mail: frederic.becq@univ-poitiers.fr.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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