ABCMdb

PMID: 19019741

Tang L, Fatehi M, Linsdell P
Mechanism of direct bicarbonate transport by the CFTR anion channel.
J Cyst Fibros. 2009 Mar;8(2):115-21. Epub 2008 Nov 18., [PubMed]

Sentences

No. Mutations Sentence Comment

94 ABCC7 p.Lys95Gln ABCC7 p.Arg303Gln Fig. 4 shows that these same charge-neutralizing mutations (K95Q, R303Q) also drastically reduce the ability of these inhibitors to block HCO3 - currents under the same ionic conditions used in Fig. 3 (50 mM HCO3 - intracellular, 50 mM gluconate extracellular). Login to comment 95 ABCC7 p.Lys95Gln Removal of one important positive charge in the K95Q mutant resulted in only small HCO3 - currents that were often difficult to resolve, nevertheless, Fig. 4 indicates that this mutation dramatically reduced the ability of both DNDS and glibenclamide to block HCO3 - currents. Login to comment 96 ABCC7 p.Arg303Gln Another mutation, R303Q, greatly weakened the blocking effects of suramin on HCO3 - currents. Login to comment 101 ABCC7 p.Gly178Arg ABCC7 p.His620Gln Fig. 5 shows macroscopic currents carried by three of these mutants, two associated with loss of cellular HCO3 - transport and PI disease (G178R, H620Q) and one with retained HCO3 - transport and PS disease (G551 S) [10]. Login to comment 103 ABCC7 p.Gly551Ser ABCC7 p.Gly551Ser ABCC7 p.Gly178Arg ABCC7 p.Gly178Arg ABCC7 p.His620Gln ABCC7 p.His620Gln It can be seen that each of these mutants is capable of mediating HCO3 - efflux; in fact, reversal potential measurements indicate PHCO3/PCl values of 0.289±0.038 (n=3) for G178R, 0.264±0.035 (n=3) for G551S, and 0.237±0.033 (n=3) for H620Q, none of which were significantly different from the value of 0.250±0.037 (n=4) estimated from wild type under the same conditions (see Fig. 1B). Login to comment 138 ABCC7 p.Gly551Ser ABCC7 p.Gly178Arg ABCC7 p.His620Gln Bicarbonate permeability of CF mutant forms of CFTR Example leak-subtracted macroscopic I-V relationships for G178R, G551S, and H620Q-CFTR under the same ionic conditions used in Fig. 1B. Login to comment 140 ABCC7 p.Lys95Gln ABCC7 p.Arg303Gln Mutations in the pore decrease the blocker sensitivity of bicarbonate currents (A) Example leak-subtracted I-V relationship recorded under the same ionic conditions used in Fig. 3B in K95Q-CFTR (left, centre panels) or R303Q-CFTR (right panel). Login to comment 146 ABCC7 p.Gly551Ser ABCC7 p.Gly178Arg ABCC7 p.His620Gln Our direct measurements of CFTR HCO3 - currents also showed no change in HCO3 - permeability in three CF-associated CFTR mutants (G178R, G551S, H620Q; Fig. 5) that were previously associated with different effects on cellular HCO3 - transport relative to Cl- transport [10]. Login to comment 147 ABCC7 p.Gly178Arg ABCC7 p.Gly178Arg ABCC7 p.His620Gln ABCC7 p.His620Gln This result suggests that loss of direct HCO3 - permeation through the channel is not responsible for the selective loss of HCO3 - transport relative to Cl- transport previously associated with the severe, PI mutations G178R and H620Q. Login to comment