Oocytes of the South African clawed toad Xenopus laevis are widely used for the heterologous expression and characterization of CFTR, the Cl- channel and central regulatory protein defect in cystic fibrosis. Here we show that the intracellular Na+ concentration ([Na+ ]i) strongly influences protein expression with CFTR serving as an instance. ENaC was co-expressed with CFTR to control [Na+ ]i. CFTR protein expression measured as ICFTR and GCFTR is the highest at [Na+ ]i of 10 mM; lower and higher [Na+ ]i drastically decrease CFTR expression. This effect is dependent on Na+ transport across the oocyte membrane since both the addition of amiloride, a potent blocker of ENaC, and removal of Na+ from the incubation medium prevented up- regulation of CFTR protein expression. Controlling [Na+ ]i by activating the endogenous Na+ /glucose cotransporter showed the same effects on CFTR protein expression. Fluorescence measurements using GFP tagged CFTR yielded the same dependence on [Na+ ]i. From these data and from results obtained with other transport proteins (ENaC, SGLT1) we conclude that [Na+ ]i controls protein expression on the translational and/or posttranslational level. Since the same influences of Na+ on protein expression has been shown in a cell free system too, we suggest that this mechanism is not unique to oocytes but could be more ubiquitous.