© 1997 American Heart Association, Inc.
Articles |
A Role for Ca2+/Calmodulin-Dependent Protein Kinase II in the Mitogen-Activated Protein Kinase Signaling Cascade of Cultured Rat Aortic Vascular Smooth Muscle Cells
From the Weis Center for Research, Geisinger Clinic, Danville, Pa.
Correspondence to Harold A. Singer, PhD, Henry Hood MD Research Program, Weis Center for Research, PennState College of Medicine, 100 N Academy Ave, Danville, PA 17822-2612.
Abstract Exposure of cultured rat aortic vascular smooth
muscle (VSM) cells to the Ca2+ ionophore ionomycin produced
an increase in extracellular signal–regulated kinase 1/2 (ERK1/2)
activity that was maximal between 2 and 5 minutes but then declined to
basal values within 20 minutes of stimulation. Elevation of
[Ca2+]i in VSM cells leads to an even more
rapid activation of Ca2+/calmodulin-dependent
protein kinase II (CaM kinase II); thus, it was postulated that the
Ca2+-dependent component of ERK1/2 activation was mediated
by CaM kinase II. Transient ERK1/2 activation by ionomycin was almost
completely abolished by pretreating cells with 30 µmol/L KN-93,
a CaM kinase II inhibitor. Treatment of cells with KN-93
did not antagonize the ability of ionomycin to mobilize intracellular
Ca2+ but prevented CaM kinase II and ERK1/2 activation with
almost identical potencies. Consistent with a role for
Ca2+ and calmodulin in intracellular
Ca2+–induced activation of ERK, cells pretreated with
calmodulin inhibitors (W-7 or
calmidazolium) exhibited an attenuated ERK response
to ionomycin. ERK1/2 activation in response to phorbol esters and
platelet-derived growth factor were not significantly affected by
KN-93, whereas the response to angiotensin II and thrombin
were attenuated by 60% and 40%, respectively. Transient expression of
wild-type 
2 CaM kinase II in COS-7 cells resulted in
increased ERK2 activity, whereas coexpression of wild-type and a
kinase-negative mutant resulted in a diminution of this response. These
data suggest that regulation of cellular responses by
Ca2+-dependent pathways in VSM cells may be mediated in
part by CaM kinase II–dependent activation of ERK1/2.
Key Words: Ca2+/calmodulin-dependent protein kinase II • Ca2+ • mitogen-activated protein kinase • extracellular signal–regulated kinase • vascular smooth muscle
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