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G-protein-mediated signaling in cholesterol-enriched arterial smooth muscle cells. 2. Role of protein kinase C-δ in the regulation of eicosanoid production

Biochemistry, ISSN: 0006-2960, Vol: 36, Issue: 31, Page: 9532-9539
1997
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Article Description

PGI generation by the vessel wall is an agonist for cyclic-AMP- dependent cholesteryl ester hydrolysis. The process of enhanced PGI synthesis is stimulated, in part, by G-protein-coupled receptor ligands. Cellular cholesterol enrichment has been hypothesized to alter G-protein- mediated PGI synthesis. In the studies reported herein, cells generated PGI in response to A1F, GTPγS, and ATP in a dose-dependent manner. G- protein agonists stimulated eicosanoid production principally by activating phospholipase A, but not phospholipase C. This is in contrast to PDGF, which stimulated phospholipase A and PLCγ activities. Gαi subunits mediate G-protein agonist-induced PGI synthesis, since ATP- and PDGF- induced PGI synthesis was inhibited by pertussis toxin. Although cholesterol enrichment reduced arachidonic acid- and PDGF-induced PGI synthesis, cholesterol enrichment enhanced PGI release in response to AlF, GTPγS, and ATP. The enhancement of PGI release in cholesterol- enriched cells was augmented by mevalonate, which inhibits the ability of cholesterol enrichment to reduce membrane-associated G-protein subunits. Since cholesterol enrichment inhibited PDGF and AIF induced MAP kinase activity [Pomerantz, K., Lander, H. M., Summers, B., Robishaw, J. D., Balcueva, E. A., and Hajjar, D. P. (1997) Biochemistry 36, 9523-9531] (the major mechanism by which phospholipase A is activated), these results suggest that cholesterol enrichment induces other alternative signaling pathways leading to phospholipase A activation. A PKC-dependent pathway is described herein that is involved in enhanced eicosanoid production in cholesterol-enriched cells. This conclusion is supported by two observations: (1) G-protein-linked PGI production is inhibited by calphostin, and (2) cholesterol enrichment augments the specific translocation of the δ-isoform of PKC from the cytosol to the plasma membrane following treatment of cells with phorbol ester. These data support the concept that, in cells possessing normal levels of cholesterol, MAP-kinase-dependent pathways mediate eicosanoid synthesis in response to G-protein activation; however, under conditions of high cellular cholesterol levels, augmented G-protein-linked eicosanoid production results from enhanced PKCδ activity.

Bibliographic Details

Kenneth B. Pomerantz; Barbara Summers; Harry M. Lander; David P. Hajjar

American Chemical Society (ACS)

Biochemistry, Genetics and Molecular Biology

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