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Vol. 298, Issue 1, 331-338, July 2001
Department of Pharmacology, University of Tennessee, Memphis,
Tennessee
SB203580
[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole]
is widely used as a specific inhibitor of p38 mitogen-activated protein
kinase (MAPK). Here we report that SB203580, which blocked p38 kinase
activation elicited by anisomycin, increased the phosphorylation and
activity of cytosolic phospholipase A2 (cPLA2)
and arachidonic acid (AA) release in quiescent vascular smooth muscle
cells from rabbit aortae. SB203580 also increased the activity of
calcium (Ca2+)/camodulin-dependent kinase II (CaMKII) and
ERK1/2 MAPK. The increase in CaMKII activity and cPLA2
phosphorylation caused by SB203580 was attenuated by CaMKII inhibitor
KN-93, indicating involvement of CaMKII in cPLA2
phosphorylation by this compound. Since KN-93 also inhibited
SB203580-induced ERK1/2 activation, it appears that ERK1/2 activation
is also mediated by CaMKII. SB203580-induced cPLA2
phosphorylation was inhibited by depletion of Ca2+ from the
medium, by the voltage-operated Ca2+ channel blocker
nifedipine, and by the calmodulin inhibitor W-7. cPLA2
translocation from cytoplasm to the nuclear envelope caused by SB203580
was also inhibited in the absence of extracellular Ca2+.
Other p38 kinase inhibitors, SB202190 and PD169316, failed to alter
CaMKII, ERK1/2, and cPLA2 activity or cPLA2
translocation to the nuclear envelope. These data suggest that SB203580
not only inhibits p38 kinase activity but also increases
Ca2+ influx through voltage-sensitive Ca2+
channels, which promotes cPLA2 translocation to the nuclear
envelope, and by interacting with calmodulin, activates CaMKII and
cPLA2 and releases AA.
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