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General Physiology and Biophysics Vol.43, No.3, p 197–207, 2024 |
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Title: Trivalent anions as probes of the CFTR channel pore | ||
Author: Paul Linsdell | ||
Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel uses positively charged amino-acid side-chains to form binding sites for permeating anions. These binding sites have been investigated experimentally using a number of anionic probes. Mutations that alter the distribution of positive and negative charges within the pore have differential effects on the binding of monovalent versus divalent anions. This study uses patch clamp recording from wild-type and pore-mutant forms of CFTR to investigate small trivalent anions (Co(NO2)63−, Co(CN)63− and IrCl63−) as potential probes of anion binding sites. These anions caused weak block of Cl− permeation in wild-type CFTR (Kd ≥ 700 μM) when applied to the intracellular side of the membrane. Mutations that increase the density of positive charge within the pore (E92Q, I344K, S1141K) increased the binding affinity of these anions 80–280-fold, and also greatly increased the voltage-dependence of block, consistent with fixed charges in the pore affecting monovalent : multivalent anion selectivity. However, high-affinity pore block by Co(NO2)63− apparently did not alter channel gating, a hallmark of high-affinity binding of divalent Pt(NO2)42− ions within the pore. This work increases the arsenal of probes available to investigate anion binding sites within Cl− channel pores. |
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Keywords: Anion selectivity — Channel block — Chloride channel — Cystic fibrosis transmembrane conductance regulator — Ion binding | ||
Published online: 14-May-2024 | ||
Year: 2024, Volume: 43, Issue: 3 | Page From: 197, Page To: 207 | |
doi:10.4149/gpb_2024007 |
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