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1 Department of Physiology, McGill University, Montreal, Quebec H3G 1Y6; 2 Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 0W0; and 3 S. C. Johnson Medical Research Center, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259
Cystic fibrosis
transmembrane conductance regulator (CFTR)
Cl
channel activity
declines rapidly when excised from transfected Chinese hamster ovary
(CHO) or human airway cells because of membrane-associated phosphatase
activity. In the present study, we found that CFTR channels usually
remained active in patches excised from baby hamster kidney (BHK) cells
overexpressing CFTR. Those patches with stable channel activity were
used to investigate the regulation of CFTR by exogenous protein
phosphatases (PP). Adding PP2A, PP2C, or alkaline phosphatase to
excised patches reduced CFTR channel activity by >90% but did not
abolish it completely. PP2B caused weak deactivation, whereas PP1 had
no detectable effect on open probability
(Po).
Interestingly, the time course of deactivation by PP2C was identical to
that of the spontaneous rundown observed in some patches after
excision. PP2C and PP2A had distinct effects on channel gating;
Po declined
during exposure to exogenous PP2C (and during spontaneous rundown, when
it was observed) without any change in mean burst duration. By
contrast, deactivation by exogenous PP2A was associated with a dramatic
shortening of burst duration similar to that reported previously in
patches from cardiac cells during deactivation of CFTR by endogenous
phosphatases. Rundown of CFTR-mediated current across intact T84
epithelial cell monolayers was insensitive to toxic levels of the PP2A
inhibitor calyculin A. These results demonstrate that exogenous PP2C is a potent regulator of CFTR activity, that its effects on single-channel gating are distinct from those of PP2A but similar to those of endogenous phosphatases in CHO, BHK, and T84 epithelial cells, and that
multiple protein phosphatases may be required for complete deactivation
of CFTR channels.
cystic fibrosis; protein phosphatase; channel rundown; cystic fibrosis transmembrane conductance regulator
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