Interactions between Impermeant Blocking Ions in the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Pore: Evidence for Anion-Induced Conformational Changes

Interactions between Impermeant Blocking Ions in the Cystic Fibrosis Transmembrane Conductance... It is well known that extracellular Cl− ions can weaken the inhibitory effects of intracellular open channel blockers in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel pore. This effect is frequently attributed to repulsive ion-ion interactions inside the pore. However, since Cl− ions are permeant in CFTR, it is also possible that extracellular Cl− ions are directly competing with intracellular blocking ions for a common binding site; thus, this does not provide direct evidence for multiple, independent anion binding sites in the pore. To test for the possible through-space nature of ion-ion interactions inside the CFTR pore, we investigated the interaction between impermeant anions applied to either end of the pore. We found that inclusion of low concentrations of impermeant Pt(NO2) 4 2− ions in the extracellular solution weaken the blocking effects of three different intracellular blockers [Pt(NO2) 4 2− , glibenclamide and 5-nitro-2-(3-phenylpropylamino)benzoic acid] without affecting their apparent voltage dependence. However, the effects of extracellular Pt(NO2) 4 2− ions are too strong to be accounted for by simple competitive models of ion binding inside the pore. In addition, extracellular Fe(CN) 6 3− ions, which do not appear to enter the pore, also weaken the blocking effects of intracellular Pt(NO2) 4 2− ions. In contrast to previous models that invoked interactions between anions bound concurrently inside the pore, we propose that Pt(NO2) 4 2− and Fe(CN) 6 3− binding to an extracellularly accessible site outside of the channel permeation pathway alters the structure of an intracellular anion binding site, leading to weakened binding of intracellular blocking ions. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Membrane Biology Springer Journals

Interactions between Impermeant Blocking Ions in the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Pore: Evidence for Anion-Induced Conformational Changes

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Publisher
Springer-Verlag
Copyright
Copyright © 2006 by Springer Science+Business Media, Inc.
Subject
Life Sciences; Human Physiology; Biochemistry, general
ISSN
0022-2631
eISSN
1432-1424
D.O.I.
10.1007/s00232-005-7028-2
Publisher site
See Article on Publisher Site

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