Potent inhibition of the CFTR chloride channel by suramin

Abstract.

After phosphorylation by protein kinase A and in the presence of ATP, the cystic fibrosis transmembrane conductance regulator (CFTR) functions as a Cl^– channel. In this study we have examined the effects of suramin on the CFTR Cl^– current (I_CFTR) in excised inside-out macropatches from Xenopus oocytes expressing human CFTR; glibenclamide, the standard inhibitor of I_CFTR, and some congeners were tested in comparison.

I_CFTR was activated by addition of the catalytic subunit of protein kinase A and MgATP to the bath. Suramin inhibited I_CFTR with an IC₅₀ value of 1 µM and a Hill coefficient close to 1; the inhibition showed little voltage dependence and was easily reversed upon washout of the drug. In comparison, glibenclamide inhibited I_CFTR with an IC₅₀ value of ≈20 µM. When tested against I_CFTR in whole oocytes, bath application of suramin was ineffective whereas glibenclamide was about four times weaker than in the inside-out patch configuration.

The data show that suramin is the most potent inhibitor of CFTR yet described and suggest that the compound approaches its site of action from the cytosol.