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 pHi and/or current in CFTR-expressing Xenopus oocytes revealed dynamic control of CFTR Cl -/HCO3- permeability ratio, which is regulated by external Cl- (Clo-). 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 pHo to 9.0 was observed only after the switch in membrane potential. The time to switch increased to 11 min at Clo- 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.
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