9314839

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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 Ca(2+)-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 mumol/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 Ca(2+)-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 delta 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 Ca(2+)-dependent pathways in VSM cells may be mediated in part by CaM kinase II-dependent activation of ERK1/2.

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0009-7330

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575-84

pubmed-meshheading:9314839-Animals, pubmed-meshheading:9314839-Aorta, pubmed-meshheading:9314839-Benzylamines, pubmed-meshheading:9314839-Calcium-Calmodulin-Dependent Protein Kinase Type 2, pubmed-meshheading:9314839-Calcium-Calmodulin-Dependent Protein Kinases, pubmed-meshheading:9314839-Cells, Cultured, pubmed-meshheading:9314839-Enzyme Activation, pubmed-meshheading:9314839-Enzyme Induction, pubmed-meshheading:9314839-Enzyme Inhibitors, pubmed-meshheading:9314839-Ionomycin, pubmed-meshheading:9314839-Ionophores, pubmed-meshheading:9314839-Mitogen-Activated Protein Kinase 1, pubmed-meshheading:9314839-Mitogen-Activated Protein Kinase 3, pubmed-meshheading:9314839-Mitogen-Activated Protein Kinases, pubmed-meshheading:9314839-Mitogens, pubmed-meshheading:9314839-Muscle, Smooth, Vascular, pubmed-meshheading:9314839-Protein Kinase Inhibitors, pubmed-meshheading:9314839-Protein Kinases, pubmed-meshheading:9314839-Rats, pubmed-meshheading:9314839-Rats, Sprague-Dawley, pubmed-meshheading:9314839-Signal Transduction, pubmed-meshheading:9314839-Sulfonamides

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.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't