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J. Biol. Chem., Vol. 282, Issue 52, 37545-37555, December 28, 2007

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State-dependent Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channels by a Novel Peptide Toxin^*

Matthew D. Fuller¹, Christopher H. Thompson, Zhi-Ren Zhang², Cody S. Freeman, Eszter Schay^¶, Gergely Szakács^¶||, Éva Bakos^¶, Balázs Sarkadi^||, Denis McMaster^**, Robert J. French^**3, Jan Pohl, Julia Kubanek^¶¶, and Nael A. McCarty⁴

From the Program in Molecular and Systems Pharmacology, Emory University, Atlanta, Georgia 30322, the School of Biology, Georgia Institute of Technology, Atlanta, Georgia 30332, the ^¶Institute of Enzymology, Hungarian Academy of Sciences, 1113 Budapest, Hungary, the ^||National Medical Center, Institute of Haematology and Immunology, Hungarian Academy of Sciences, 1113 Budapest, Hungary, the ^**Peptide Synthesis Core Facility, University of Calgary, Calgary, Alberta T2N 4N1, Canada, the Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta T2N 4N1, Canada, the Microchemical and Proteomics Facility, Emory University, Atlanta, Georgia 30322, and the ^¶¶School of Chemistry & Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332

Peptide toxins from animal venom have been used for many years for the identification and study of cation-permeable ion channels. However, no peptide toxins have been identified that interact with known anion-selective channels, including cystic fibrosis transmembrane conductance regulator (CFTR), the protein defective in cystic fibrosis and a member of the ABC transporter superfamily. Here, we describe the identification and initial characterization of a novel 3.7-kDa peptide toxin, GaTx1, which is a potent and reversible inhibitor of CFTR, acting from the cytoplasmic side of the membrane. Thus, GaTx1 is the first peptide toxin identified that inhibits a chloride channel of known molecular identity. GaTx1 exhibited high specificity, showing no effect on a panel of nine transport proteins, including Cl^- and K⁺ channels, and ABC transporters. GaTx1-mediated inhibition of CFTR channel activity is strongly state-dependent; both potency and efficacy are reduced under conditions of elevated [ATP], suggesting that GaTx1 may function as a non-competitive inhibitor of ATP-dependent channel gating. This tool will allow the application of new quantitative approaches to study CFTR structure and function, particularly with respect to the conformational changes that underlie transitions between open and closed states.

Received for publication, September 27, 2007

^* This research was supported by the National Institutes of Health (NIH), the NIH-NCRR, the National Science Foundation, the Canadian Institutes of Health Research, and the Cystic Fibrosis Foundation. The GaTx1 sequence has been deposited at UniProt, as entry P85066. This technology is protected by a pending international patent, #PCT/US2007/069243, held by Georgia Tech Research Corporation. We declare no competing interests. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S5 and Table S1.

¹ Current address: Dept. of Pharmacology, University of Washington, Seattle, WA 98195.

² Current address: Div. of Nephrology, Medical University of South Carolina, Charleston, SC 29425.

³ An Alberta Heritage Foundation for Medical Research Medical Scientist.

⁴ To whom correspondence should be addressed: 310 Ferst Dr., Atlanta, GA 30332-0230. Tel.: 404-385-2955; Fax: 404-385-2955; E-mail: mccarty{at}gatech.edu or nael_mccarty{at}oz.ped.emory.edu.

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