TY - JOUR
T1 - State-dependent inhibition of cystic fibrosis transmembrane conductance regulator chloride channels by a novel peptide toxin
AU - Fuller, Matthew D.
AU - Thompson, Christopher H.
AU - Zhang, Zhi Ren
AU - Freeman, Cody S.
AU - Schay, Eszter
AU - Szakács, Gergely
AU - Bakos, Éva
AU - Sarkadi, Balázs
AU - McMaster, Denis
AU - French, Robert J.
AU - Pohl, Jan
AU - Kubanek, Julia
AU - McCarty, Nael A.
PY - 2007/12/28
Y1 - 2007/12/28
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M708079200
DO - 10.1074/jbc.M708079200
M3 - Article
C2 - 17951250
AN - SCOPUS:38049166041
SN - 0021-9258
VL - 282
SP - 37545
EP - 37555
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 52
ER -