Alkyl analogs of diacylglycerol as activators of protein kinase C

Heymans, Françoise; Silva, Corinne Da; Marrec, Noël; Godfroid, Jean‐Jacques; Castagna, Monique

doi:10.1016/0014-5793(87)81013-x

Cited by 59 publications

(16 citation statements)

References 24 publications

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“…The fatty acid moieties involved in 1,2-DAG accumulation in tissue may not be equivalent activators of protein kinease C, since exogenous additions of 1,2-DAG and analogs have different biological potentials for activating protein kinase C (35,36). In the present study, analysis of the fatty acid composition of 1,2-DAG in the myocardium indicated no difference between the strains at the ages examined.…”

Section: Discussioncontrasting

confidence: 51%

1,2-Diacylglycerol content in myocardium from spontaneously hypertensive rats during the development of hypertension

et al. 1990

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1,2-Diacylglycerol (DAG) has been considered to play an important role as an activator of protein kinase C in the signal transduction of inositol phospholipid metabolism. To examine the relation of 1,2-DAG in heart tissues to cardiac hypertrophy associated with hypertension, we measured the amount of 1,2-DAG in spontaneously hypertensive rat (SHR) hearts at 4, 10 and 20 weeks of age, and in age-matched normotensive Wistar-Kyoto (WKY) rat hearts using thin-layer chromatography with flame ionization detection (TLC-FID). Significant cardiac hypertrophy was found in 4-week-old SHR, while SHR did not yet have significant hypertension. Major phospholipids such as phosphatidylcholine and phosphatidylethanolamine increased from 4 to 20 weeks in the myocardium, but there was no difference between the two strains. The cholesterol levels of 4- and 20-week-old SHR were significantly higher than WKY rats. The 1,2-DAG contents of SHR hearts were significantly higher than WKY rats at 4 weeks. An increase in the RNA content was also observed in 4-week-old SHR hearts. However, analysis of the fatty acid composition of 1,2-DAG revealed no difference between the two strains. However, there was no significant difference in the 1,2-DAG content or in its fatty acid composition between SHR and WKY rat hearts at 10 and 20 weeks of age. It is suggested that an increase in the 1,2-DAG content of SHR hearts during the early stages appears related to the initiation of cardiac hypertrophy in SHR hearts before developed hypertension.

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Section: Discussioncontrasting

confidence: 51%

1,2-Diacylglycerol content in myocardium from spontaneously hypertensive rats during the development of hypertension

et al. 1990

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“…The results from that report indicate that the 1-O-alkylglycerol portion of LPG is primarily responsible for the inhibitory activity. This was not unexpected, since ether-for-acyl substitutions have been reported to result in a potent decrease in PKC-activating ability [15,16]. The type of inhibition displayed by the 1-O-alkylglycerol appears to be complex with respect to diolein concentration, since both the apparent Km and Vmax were affected.…”

Section: Discussionmentioning

confidence: 83%

Inhibitory effects on protein kinase C activity by lipophosphoglycan fragments and glycosylphosphatidylinositol antigens of the protozoan parasite Leishmania

McNeely

Rosen²,

Londner³

et al. 1989

Biochemical Journal

123

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Fragments of the lipophosphoglycan of Leishmania donovani were generated by phospholipase C digestion and mild acid hydrolysis. The fragments were purified and examined for inhibitory activity on protein kinase C isolated from rat brains. On a molar basis, the 1-O-alkylglycerol portion of LPG exhibited the most inhibitory activity, whereas the carbohydrate domain was not as effective. In addition, several glycolipid antigens from L. major, which contain short carbohydrate chains attached to phosphatidylinositol, were also efficient inhibitors of the enzyme. These results are consistent with the hypothesis that protein kinase C may be a key target for the parasites to overcome within host macrophages.

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“…In fact, ether-linked DG may competitively inhibit PKC activation induced by diacylglycerol species (4). Additional studies support this signaling mechanism, as ether-linked DG fail to activate total PKC activity in vitro or only activate PKC in the presence of pharmacological concentrations of calcium (5)(6)(7)(8).…”

mentioning

confidence: 99%

Interleukin-1-induced Ether-linked Diglycerides Inhibit Calcium-insensitive Protein Kinase C Isotypes

Mandal¹,

Wang²,

Ernsberger³

et al. 1997

Journal of Biological Chemistry

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It is hypothesized that inflammatory cytokines and vasoactive peptides stimulate distinct species of diglycerides that differentially regulate protein kinase C isotypes. In published data, we demonstrated that interleukin-1, in contrast to endothelin, selectively generates ether-linked diglyceride species (alkyl, acyl-and alkenyl, acylglycerols) in rat mesangial cells, a smooth muscle-like pericyte in the glomerulus. We now demonstrate both in intact cell and in cell-free preparations that these interleukin-1 receptor-generated ether-linked diglycerides inhibit immunoprecipitated protein kinase C ␦ and ⑀ but not activity. Neither interleukin-1 nor endothelin affect de novo protein expression of these protein kinase C isotypes. As down-regulation of calciuminsensitive protein kinase C isotypes has been linked to antimitogenic activity, we investigated growth arrest as a functional correlate for IL-1-generated ether-linked diglycerides. Cell-permeable ether-linked diglycerides mimic the effects of interleukin-1 to induce a growtharrested state in both G-protein-linked receptor-and tyrosine kinase receptor-stimulated mesangial cells. This signaling mechanism implicates cytokine receptorinduced ether-linked diglycerides as second messengers that inhibit the bioactivity of calcium-insensitive protein kinase C isotypes resulting in growth arrest.Interleukin-1 (IL-1) 1 -induced activation of rat glomerular mesangial cells (MC) culminates in an inflammatory phenotype often observed in vivo in models of glomerulosclerosis. Our laboratory has been investigating the early, lipid-mediated signal transduction pathways for inflammatory cytokines in MC with particular emphasis on the distinct molecular species of diglycerides (DG) generated and their regulation of protein kinase C (PKC) activity. We have demonstrated previously that the inflammatory cytokine interleukin-1␣ and the vasoconstrictor peptide, endothelin-1 (ET-1) generate distinct species of DG from different membrane-associated phospholipids in MC (1-3). IL-1 receptor activation selectively generates etherlinked species of DG, namely alkyl, acyl-and alkenyl, acylglycerols, whereas ET-1 receptor activation produces predominantly ester-linked diacylglycerols (1). Our laboratory has also demonstrated previously that these IL-1 generated etherlinked DG, in contrast to the PKC-activating diacylglycerols, inhibit total PKC activity as well as inhibit diacylglycerolstimulated PKC ␣ activation (1). In fact, ether-linked DG may competitively inhibit PKC activation induced by diacylglycerol species (4). Additional studies support this signaling mechanism, as ether-linked DG fail to activate total PKC activity in vitro or only activate PKC in the presence of pharmacological concentrations of calcium (5-8).In light of these findings, our interest has now turned to regulation by ether-linked DG of specific PKC isotypes. The PKC family now includes 12 distinct isotypes subdivided into three categories (9). The calcium-sensitive conventional PKCs consist of alpha (␣), beta (␤ 1 ...

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Alkyl analogs of diacylglycerol as activators of protein kinase C

Cited by 59 publications

References 24 publications

1,2-Diacylglycerol content in myocardium from spontaneously hypertensive rats during the development of hypertension

1,2-Diacylglycerol content in myocardium from spontaneously hypertensive rats during the development of hypertension

Inhibitory effects on protein kinase C activity by lipophosphoglycan fragments and glycosylphosphatidylinositol antigens of the protozoan parasite Leishmania

Interleukin-1-induced Ether-linked Diglycerides Inhibit Calcium-insensitive Protein Kinase C Isotypes

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