The influence of ether lipid (AMG) on histamine release from isolated rat mast cells: synergistic interaction with TPA indicates protein kinase C activation

Grosman, Nina

doi:10.1016/0162-3109(90)90017-9

Cited by 5 publications

(2 citation statements)

References 17 publications

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“…Thus, the presence of HAG alone in vesicles was found to have only negligible effects on the activities of each PKC isoform, whereas in the presence of either TPA or OAG, HAG enhanced conventional PKC isozyme activity but had no effect on PKCδ activity. The present results also provide a possible explanation for the synergism that exists between phorbol ester and HAG effects on mast cell histamine release (54,55).…”

Section: Discussionsupporting

confidence: 61%

Low- and High-Affinity Phorbol Ester and Diglyceride Interactions with Protein Kinase C: 1-O-Alkyl-2-acyl-sn-glycerol Enhances Phorbol Ester- and Diacylglycerol-Induced Activity but Alone Does Not Induce Activity

et al. 2001

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Phorbol ester-induced conventional protein kinase C (PKCalpha, -betaIota/IotaIota, and -gamma) isozyme activities are potentiated by 1,2-diacyl-sn-glycerol. This has been attributed to a "cooperative" interaction of the two activators with two discrete sites termed the low- and high-affinity phorbol ester binding sites, respectively [Slater, S. J., Milano, S. K., Stagliano, B. A., Gergich, K. J., Ho, C., Mazurek, A., Taddeo, F. J., Kelly, M. B., Yeager, M. D., and Stubbs, C. D. (1999) Biochemistry 38, 3804-3815]. Here, we report that the 1-O-alkyl ether diglyceride, 1-O-hexadecyl-2-acetyl-sn-glycerol (HAG), like its 1,2-diacyl counterpart, 1-oleoyl-2-acetyl-sn-glycerol (OAG), also potentiated PKCalpha, -betaI/II, and -gamma activities induced by the phorbol ester 4beta-12-O-tetradecanoylphorbol-13-acetate (TPA). Similar to OAG, HAG was found to bind to the low-affinity phorbol ester binding site and to enhance high-affinity phorbol ester binding, and to decrease the level of Ca(2+) required for phorbol ester-induced activity, while being without effect on the Ca(2+) dependence of membrane association. Thus, similar to OAG, HAG may also potentiate phorbol ester-induced activity by interacting with the low-affinity phorbol ester binding site, leading to a reduced level of Ca(2+) required for the activating conformational change. However, HAG was found not to behave like a 1,2-diacyl-sn-glycerol in that alone it did not induce PKC activity, and also in that it enhanced OAG-induced activity. The results reveal HAG to be a member of a new class of "nonactivating" compounds that modulate PKC activity by interacting with the low-affinity phorbol ester binding site.

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Section: Discussionsupporting

confidence: 61%

Low- and High-Affinity Phorbol Ester and Diglyceride Interactions with Protein Kinase C: 1-O-Alkyl-2-acyl-sn-glycerol Enhances Phorbol Ester- and Diacylglycerol-Induced Activity but Alone Does Not Induce Activity

et al. 2001

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“…A potential role for miltefosine in allergic disease was suggested when it was shown that miltefosine can reduce histamine release from rat primary mast cells (Grosman 1990). Mast cells contain large granules with inflammatory mediators such as cytokines, proteases, histamine, serotonin, and eicosanoids.…”

Section: Miltefosine and Allergic Diseasementioning

confidence: 99%

Repurposing Miltefosine for the Treatment of Immune-Mediated Disease?

Verhaar

Wildenberg

Peppelenbosch

et al. 2014

J Pharmacol Exp Ther

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Miltefosine is an ether lipid that was initially developed for cancer treatment in the early 1980s. Miltefosine largely failed development for oncology, although it was approved for the topical treatment of breast cancer metastasis. It was subsequently discovered that miltefosine is a highly effective treatment of visceral Leishmaniasis, a parasitic disease that affects millions worldwide and causes an estimated 30,000 fatalities each year. Oral treatment with miltefosine is generally well tolerated and has relatively few adverse effects. The exact mechanism of action of miltefosine treatment is still under investigation. Its close resemblance to phospholipids allows it to be quickly taken up by cell membranes and affect related processes, such as lipid metabolism and signaling through lipid rafts. These processes play an important role in the immune response and it comes as no surprise that miltefosine has been successfully tested for the treatment of a number of immune-mediated diseases in preclinical models of disease. Drug repurposing of miltefosine for immunemediated diseases may provide an opportunity to expand the limited number of drugs that are currently available for therapeutic use.

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Effects of the ether phospholipid AMG-PC on mast cells are similar to that of the ether lipid AMG but different from that of the analogue hexadecylphosphocholine

Grosman

1991

Immunopharmacology

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The influence of ether lipid (AMG) on histamine release from isolated rat mast cells: synergistic interaction with TPA indicates protein kinase C activation

Cited by 5 publications

References 17 publications

Low- and High-Affinity Phorbol Ester and Diglyceride Interactions with Protein Kinase C: 1-O-Alkyl-2-acyl-sn-glycerol Enhances Phorbol Ester- and Diacylglycerol-Induced Activity but Alone Does Not Induce Activity

Low- and High-Affinity Phorbol Ester and Diglyceride Interactions with Protein Kinase C: 1-O-Alkyl-2-acyl-sn-glycerol Enhances Phorbol Ester- and Diacylglycerol-Induced Activity but Alone Does Not Induce Activity

Repurposing Miltefosine for the Treatment of Immune-Mediated Disease?

Effects of the ether phospholipid AMG-PC on mast cells are similar to that of the ether lipid AMG but different from that of the analogue hexadecylphosphocholine

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