Dynamic control of cystic fibrosis transmembrane conductance regulator Cl^-/HCO₃^- selectivity by external Cl ^-

HCO₃^- secretion is a vital activity in cystic fibrosis transmembrane conductance regulator (CFTR)-expressing epithelia. However, the role of CFTR in this activity is not well understood. Simultaneous measurements of membrane potential and pH_i and/or current in CFTR-expressing Xenopus oocytes revealed dynamic control of CFTR Cl ^-/HCO₃^- permeability ratio, which is regulated by external Cl^- (Cl_o^-). Thus, reducing external Cl^- from 110 to 0-10 mM resulted in the expected increase in membrane potential, but with no corresponding OH^- or HCO ₃^- influx. Approximately 3-4 min after reducing Cl _o^- to 0 mM, an abrupt switch in membrane potential occurs that coincided with an increased rates of OH^- and HCO ₃^- influx. The switch in membrane permeability to OH ^-/HCO₃^- can also be recorded as a leftward shift in the reversal potential. Furthermore, an increased rate of OH ^- influx in response to elevating pH_o to 9.0 was observed only after the switch in membrane potential. The time to switch increased to 11 min at Cl_o^- of 5 mM. Conversely, re-addition of external Cl^- after the switch in membrane potential did not stop HCO ₃^- influx, which continued for about 3.9 min after Cl ^- addition. Importantly, addition of external Cl^- to cells incubated in Cl^--free medium never resulted in HCO ₃^- efflux. Voltage and current clamp experiments showed that the delayed HCO₃^- transport is electrogenic. These results indicate that CFTR exists in two conformations, a Cl^- only and a Cl^- and OH^-/HCO₃^- permeable state. The switch between the states is controlled by external Cl^-. Accordingly, a different tryptic pattern of CFTR was found upon digestion in Cl^--containing and Cl^--free media. The physiological significance of these finding is discussed in the context of HCO ₃^- secretion by tissues such as the pancreas and salivary glands.