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  • Title: Monovalent: Divalent Anion Selectivity in the CFTR Channel Pore.
    Author: Linsdell P.
    Journal: Cell Biochem Biophys; 2021 Dec; 79(4):863-871. PubMed ID: 34031860.
    Abstract:
    The cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel shows only weak selectivity between different small monovalent anions, however, little is known about its ability to discriminate between monovalent and divalent anions. The present study uses patch clamp recording to investigate the interaction between the small divalent anions S2O32- and SO42- and wild-type and pore-mutant forms of human CFTR. Binding of these anions to wild-type CFTR appears weak; at 10 mM, intracellular S2O32- and SO42- blocked <20 and <5% of macroscopic Cl- current respectively, while these same concentrations had no discernible blocking effect when present in the extracellular solution. However, introduction of additional positive charge into the inner vestibule of the pore (in I344K and S1141K mutant channels) drastically strengthened block by intracellular (but not extracellular) S2O32- and SO42-. Block of these mutant channels was highly voltage-dependent; at very negative membrane potentials, apparent binding affinities were ~100 µM for S2O32- and <1 mM for SO42-. Permeability of S2O32- and SO42- was too small to be quantified in wild-type CFTR, but was <1% of Cl- permeability. Mutants that strengthened divalent binding (I344K, S1141K), as well as the selectivity-altering mutant F337A, also showed immeasurably low S2O32- and SO42- permeabilities. Overall CFTR selects well for monovalent over divalent anions, both in terms of binding and permeability. The number or density of fixed positive charges in the pore appears well optimized to disfavour binding of divalent anions, which may be an important facet of the monovalent Cl- permeation mechanism.
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