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 HCO3- 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 HCO3- influx. The switch in membrane permeability to OH-/ HCO(3)(-)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 HCO3- 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 HCO3- 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 HCO3- secretion by tissues such as the pancreas and salivary glands.