Apparent inhibition of S1141K at hyperpolarized voltages. (A) Example leak-subtracted macroscopic I-V relationships for the different CFTR variants named using a low extracellular Cl− concentration (4 mM). In each case, currents were recorded after stimulation with 5–10 nM PKA and 1 mM ATP (ATP), and again after the addition of 2 mM PPi (+PPi). (B and C) Relative shape of the I-V relationship in the presence of 1 mM ATP (B) or 1 mM ATP plus 2 mM PPi (C), analyzed by plotting the current at each voltage relative to the current amplitude at 0 mV, for wild type (○), S1141K (•), and K95S/S1141K (▾). (D) The effect of PPi on macroscopic current amplitude. Note that PPi causes a voltage-independent stimulation in wild type (○) and K95S/S1141K (▾), whereas in S1141K (•), PPi causes stimulation at depolarized voltages and inhibition at hyperpolarized voltages. Asterisk indicates the voltage range over which the effects of PPi on wild type and S1141K were significantly different (P < 0.05). Mean of data from four to five patches in B–D.