Function and Regulation of the Cystic Fibrosis Transmembrane 
Conductance Regulator 
of amino acids similar to those found in a number 
of proteins that utilize ATP. To determine if the 
CFTR Cl~ channel utilizes ATP, we first phos- 
phory'lated it with PKA and then examined the 
effect of ATP on cell-free membrane patches con- 
taining CFTR. We found that ATP is required for 
the channel to open. The channel appears to re- 
quire the hydrolysis of ATP; nonhydrolyzable ana- 
logues would not open it. This observation pro- 
vides the first example of an ion channel 
regulated by ATP hydrolysis. We were surprised 
because an ion channel, by its nature, is a passive 
structure. The results suggest that the energy 
from ATP hydrolysis may be required to open the 
channel and that, once open, Cl~ flows through 
passively. 
These studies have begun to define the func- 
tion of CFTR, and in so doing, they begin to ex- 
plain why the apical membrane of CF epithelia 
are impermeable to CP. They also suggest that 
correction of the underlying defect would be a 
feasible therapeutic strategy. 
In addition to the studies of the CFTR Cl~ chan- 
nel, the laboratory is investigating other channels 
in epithelial cells. Other CI" channels are not as 
well explored as the CFTR channel; but if their 
regulation were understood, they might possibly 
be utilized to bypass the CFTR CP channel de- 
fect. Potassium channels, too, are important, be- 
cause they generate the intracellular voltage that 
drives Cl~ out of the cell across the apical mem- 
brane into the airway lumen. Finally, the labora- 
tory has a major focus on the regulation of intra- 
cellular calcium. The calcium ion is known to 
regulate some CP channels in the airway epithe- 
lial cells, and again, a better understanding of this 
process might open an approach by which the CF 
defect could be circumvented. 
CI 
ATP 
ATP 
Model showing the proposed domains of the cystic fibrosis transmem- 
brane conductance regulator ( CFTR). Membrane is cross-hatched area. 
MSD refers to membrane- spanning domain, NBD to nucleotide-binding 
domain, and PKA to cAMP-dependent protein kinase. Mutation of the 
CFTR gene is responsible for the defective function of chloride channels in 
CF patients. 
Adapted from Anderson, M.P., Berger, H.A., Rich, D.P., Gregory, R.J., 
Smith, A.E., and Welsh, M.f. 1991. Cell 67:775-784. Copyright© 1991 by 
Cell Press. 
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