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stimulates CFTR activity by PKA- and PKC-dependent
phosphorylation
Departments of 1 Clinical Science and 2 Pediatrics, Alfred I. duPont Hospital for Children, Thomas Jefferson University, Wilmington, Delaware 19803
The cystic fibrosis transmembrane conductance regulator (CFTR)
can be activated by protein kinase A (PKA)- or protein kinase C
(PKC)-dependent phosphorylation. To understand how activation of both
kinases affects CFTR activity, transfected NIH/3T3 cells were
stimulated with forskolin (FSK), phorbol myristate acetate (PMA), or
prostaglandin F2
(PGF). PGF
stimulates inositol trisphosphate and cAMP production in NIH/3T3 cells.
As measured by I
efflux,
maximal CFTR activity with PGF and FSK was equivalent and fivefold
greater than that with PMA. Both PGF and PMA had additive effects on
FSK-dependent CFTR activity. PMA did not increase cellular cAMP, and
maximal PGF-dependent CFTR activity occurred with ~20% of the
cellular cAMP observed with FSK-dependent activation. Staurosporine,
but not H-89, inhibited CFTR activation and in vivo phosphorylation at
low PGF concentrations. In contrast, at high PGF concentrations, CFTR
activation and in vivo phosphorylation were inhibited by H-89. As
judged by protease digestion, the sites of in vivo CFTR phosphorylation
with FSK and PMA differed. For PGF, the data were most consistent with
in vivo CFTR phosphorylation by PKA and PKC. Our data suggest that
activation of PKC can enhance PKA-dependent CFTR activation.
protein phosphorylation; iodide efflux; phorbol ester; adenosine 3',5'-cyclic monophosphate; NIH/3T3 cells; chloride channels
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