Phosphorylation of P-glycoprotein by PKA and PKC modulates swellingactivated Cl Ϫ currents. Am. J. Physiol. 276 (Cell Physiol. 45): C370-C378, 1999.-Several proteins belonging to the ATPbinding cassette superfamily can affect ion channel function. These include the cystic fibrosis transmembrane conductance regulator, the sulfonylurea receptor, and the multidrug resistance protein P-glycoprotein (MDR1). We measured whole cell swelling-activated Cl Ϫ currents (I Cl,swell ) in parental cells and

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... lls expressing wild-type MDR1 or a phosphorylationdefective mutant (Ser-661, Ser-667, and Ser-671 replaced by Ala). Stimulation of protein kinase C (PKC) with a phorbol ester reduced the rate of increase in I Cl,swell only in cells that express MDR1. PKC stimulation had no effect on steady-state I Cl,swell . Stimulation of protein kinase A (PKA) with 8-bromoadenosine 3Ј,5Ј-cyclic monophosphate reduced steady-state I Cl,swell only in MDR1-expressing cells. PKA stimulation had no effect on the rate of I Cl,swell activation. The effects of stimulation of PKA and PKC on I Cl,swell were additive (i.e., decrease in the rate of activation and reduction in steadystate I Cl,swell ). The effects of PKA and PKC stimulation were absent in cells expressing the phosphorylation-defective mutant. In summary, it is likely that phosphorylation of MDR1 by PKA and by PKC alters swelling-activated Cl Ϫ channels by independent mechanisms and that Ser-661, Ser-667, and Ser-671 are involved in the responses of I Cl,swell to stimulation of PKA and PKC. These results support the notion that MDR1 phosphorylation affects I Cl,swell .