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Inhibit Phorbol Ester-Induced Reduction of Bradykinin-Evoked Calcium
Mobilization in A549 Cells
Isis Pharmaceuticals, Department of Molecular Pharmacology,
Carlsbad, California 92008
Regulation of the bradykinin-evoked increase in intracellular
Ca2+ concentration by protein kinase C (PKC)-
was
investigated in A549 human lung carcinoma cells. Bradykinin, a potent
and selective kinin B2 receptor agonist, induces calcium
mobilization in a concentration-dependent fashion in this cell line.
12-O-Tetradecanoylphorbol-13-acetate (TPA), a potent
activator of PKC, is known to reduce the amplitude of agonist-induced
calcium mobilization in various cell lines. Because PKC- is a major
PKC isozyme in A549 cells, we investigated whether this isozyme plays a
role in this process. A 20-mer phosphorothioate oligonucleotide
targeting the 3
-untranslated region of the human PKC- mRNA, which
contains 2-methoxyethyl modifications incorporated into the 5 and 3
segments of the oligonucleotide, was used to assess the putative role
of PKC- in the receptor regulation. ISIS 9606 reduced PKC- mRNA
for 
72 hr after the initial treatment and the reduction was
concentration dependent, whereas the mismatch control, ISIS 13009, had
no effect. Concentrations of ISIS 9606 of 150 nM
specifically reduced the level of immunoreactive PKC- protein by
66.3 ± 2.5% at 72 hr after treatment, without an effect on
immunoreactive PKC-
protein. This reduction in PKC- was
sufficient to inhibit the reduction of bradykinin-induced calcium
mobilization by TPA. This finding is corroborated by the use of
staurosporine, a nonselective PKC inhibitor, that prevented the effect
of TPA. These results suggest that PKC- is involved in kinin
B2 receptor regulation by phorbol esters in A549 cells.
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