Potent inhibition of the CFTR chloride channel by suramin

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 mu M 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 approximate to 20 mu M. 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.