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(Received for publication, November 7, 1996, and in revised form, December 15, 1996)
From the Department of Physiology, McGill University, 3655 Drummond
Street, Montréal, Québec H3G 1Y6, Canada
Protein kinase A (PKA) stimulates Cl secretion by
activating the cystic fibrosis transmembrane conductance regulator
(CFTR), a tightly regulated Cl
Volume 272, Number 8,
Issue of February 21, 1997
pp. 4978-4984
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
channel in the apical
membrane of many secretory epithelia. The CFTR channel is also
modulated by protein kinase C (PKC), but the regulatory mechanisms are
poorly understood. Here we present evidence that PKA-mediated
phosphorylation alone is not a sufficient stimulus to open the CFTR
chloride channel in the presence of MgATP; constitutive PKC
phosphorylation is essential for acute activation of CFTR by PKA. When
patches were excised from transfected Chinese hamster ovary cells, CFTR
responses to PKA became progressively smaller with time and eventually
disappeared. This decline in PKA responsiveness did not occur in the
presence of exogenous PKC and was reversed by the addition of PKC to
channels that had become refractory to PKA. PKC enhanced PKA
stimulation of open probability without increasing the number of
functional channels. Short-term pretreatment of cells with the PKC
inhibitor chelerythrine (1 µM) reduced the channel
activity that could be elicited by forskolin in cell-attached patches.
Moreover, in whole cell patches, acute stimulation of CFTR currents by
chlorophenylthio-cAMP was abolished by two chemically unrelated PKC
inhibitors, although an abrupt, partial activation was observed after a
delay of >15 min. Modulation by PKC was most pronounced when basal PKC
phosphorylation was reduced by briefly preincubating cells with
chelerythrine. Constitutive PKC phosphorylation in unstimulated cells
permits the maximum elevation of open probability by PKA to reach a
level that is ~60% of that attained during in vitro
exposure to both kinases. Differences in basal PKC activity may
contribute to the variable cAMP responsiveness of CFTR channels in
different cell types.
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J. P. Clancy, F. E. Ruiz, and E. J. Sorscher Adenosine and its nucleotides activate wild-type and R117H CFTR through an A2B receptor-coupled pathway Am J Physiol Cell Physiol, February 1, 1999; 276(2): C361 - C369. [Abstract] [Full Text] [PDF]
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D. C. GADSBY and A. C. NAIRN Control of CFTR Channel Gating by Phosphorylation and Nucleotide Hydrolysis Physiol Rev, January 1, 1999; 79(1): 77 - 107. [Abstract] [Full Text] [PDF]
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K. A. Yurko-Mauro and W. W. Reenstra Prostaglandin F2alpha stimulates CFTR activity by PKA- and PKC-dependent phosphorylation Am J Physiol Cell Physiol, September 1, 1998; 275(3): C653 - C660. [Abstract] [Full Text] [PDF]
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