Manoalide, a natural sesterterpenoid that inhibits calcium channels.

Wheeler, Larry A.; Sachs, George; Vries, G De; Goodrum, D; WoldeMussie, Elizabeth; Muallem, Shmuel

doi:10.1016/s0021-9258(18)48274-9

Cited by 60 publications

(16 citation statements)

References 19 publications

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“…In control ceils, EGF addition resulted in a broad and prolonged response (Fig. 6 A) in accordance with previous results (32,46,60). Addition of EGF in Ca2÷-free medium resulted in a single, transient peak (Fig.…”

Section: Stimulation Of Polyphosphoinositide Breakdown ~ Ssupporting

confidence: 92%

“…When extra Ca 2÷ was added to these cells, a second peak of [Ca2+]~ increase due to influx was observed (Fig. 6 B), in accordance with the results of Wheeler et al (60). EGF addition to A431-2E9 cells (Fig.…”

Section: Stimulation Of Polyphosphoinositide Breakdown ~ Ssupporting

confidence: 90%

“…In a variety of cell lines it has been found that the EGF effect is largely dependent on the presence of Ca 2÷ in the extracellular medium (46). Hepler et al (32) and Wheeler et al (60) showed that in A431 cells the EGF-induced Ca 2÷ signal is biphasic, consisting of a small, transient release of Ca 2+ from intracellular stores accompanied by a large, prolonged influx from the extracellular medium. A431 cells were labeled with indo-1, a fluorescent dye which allows detection of minor changes in [Ca2÷]:.…”

Section: Stimulation Of Polyphosphoinositide Breakdown ~ Smentioning

confidence: 99%

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Signal transduction by epidermal growth factor occurs through the subclass of high affinity receptors.

Defize

Boonstra

Meisenhelder

et al. 1989

The Journal of Cell Biology

184

125

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Abstract. Many cell types display two classes of epidermal growth factor receptor (EGFR) as judged from EGF binding studies; i.e., a major class of low affinity EGFR and a minor class of high affinity EGFR. We have studied their respective contribution to the cascade of events elicited by EGF in human A431 carcinoma cells, using anti-EGFR mAb 2E9. This antibody specifically blocks EGF binding to low affinity EGFR, without activating receptors in intact cells, and thus enables us to study the effects of exclusive EGF binding to high affinity EGFR. We show that blocking of low affinity EGFR by mAb 2E9 has almost no effect on the activation of the receptor protein-tyrosine kinase by EGF, suggesting that EGFR kinase activation occurs exclusively through the subclass of high affinity EGFR (5-10%). In addition, we provide evidence that high affinity EGFR exists both in monomeric and dimeric forms, and that cross-phosphorylation of low affinity EGFR by high affinity EGFR may take place in dimers of both receptor types.We demonstrate that the following early cellular responses to EGF are also unimpaired in the presence of mAb 2E9: (a) inositol phosphate production, (b) release of Ca ~+ from intracellular stores, (c) rise in intracellular pH, (d) phosphorylation of EGF on threonine residue 654, (e) induction of c-fos gene expression, and (f) alteration in cell morphology. As possible nonspecific side effects, we observed that the EGF induced Ca 2+ influx and fluid-phase pinocytosis were inhibited in A431 cells in the presence of mAb 2E9. We conclude, therefore, that the activation of the EGFR signal transduction cascade can occur completely through exclusive binding of EGF to the subclass of high affinity EGFR.

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Section: Stimulation Of Polyphosphoinositide Breakdown ~ Ssupporting

confidence: 92%

Section: Stimulation Of Polyphosphoinositide Breakdown ~ Ssupporting

confidence: 90%

Section: Stimulation Of Polyphosphoinositide Breakdown ~ Smentioning

confidence: 99%

See 1 more Smart Citation

Signal transduction by epidermal growth factor occurs through the subclass of high affinity receptors.

Defize

Boonstra

Meisenhelder

et al. 1989

The Journal of Cell Biology

184

125

View full text Add to dashboard Cite

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“…Isotetrandrine, which interferes with G-protein coupling to PLA # but leaves enzyme activity intact [23], also blocked 57 % of the response. Manoalide, which is not absolutely specific for PLA # and was reported to inhibit phospholipase C and Ca# + channels as well [29], inhibited 55 % of Ca# + influx at 2 µM concentration. Another potent inhibitor was ONO-RS-082 [17], whereas other reported PLA # effectors were more or less inactive (Table 1).…”

Section: Effect Of Pla 2 Inhibitorsmentioning

confidence: 96%

Mechanism of cAMP-induced Ca2+ influx in Dictyostelium: role of phospholipase A2

Schaloske

Malchow

1997

Biochemical Journal

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cAMP-induced Ca2+ influx in Dictyostelium follows two pathways: a G-protein-dependent pathway where influx is reduced by 50-70% in Galpha2 and Gbeta-negative strains and a heterotrimeric G-protein-independent pathway. Using a pharmacological approach, we found that phospholipase A2 (PLA2) is the target of both pathways. The products of PLA2 activity, arachidonic acid (AA) and palmitic acid, induced Ca2+ influx to a similar extent as cAMP. Half-maximal activation occurred at 3 microM AA and saturation at 10 microM AA. The response to AA was quantitatively similar throughout early differentiation and thus independent of cAMP-receptor concentration. Synergy experiments revealed that cAMP and AA acted through identical pathways. The PLA2-activating peptide, a peptide with sequence similarity to the G-protein beta-subunit, activated Ca2+ influx. The G-protein-independent pathway was sensitive to genistein but not to blockers of protein kinase C and other kinases, suggesting that tyrosine kinase may directly or indirectly activate PLA2 in this case.

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“…BPB (IDs0 -30-100/zM) and mepacrine (IDs0 = 0.1-0.3 mM) have been documented to inhibit phosphatidyl inositol-specific phospholipase C, and BPB also antagonizes diglyceride lipase (35,36). Manoalide may also inhibit calcium mobilization and phospholipase C (37,38). However, each of these compounds respectively inhibits platelet cytotoxicity in the appropriate concentration ranges documented to be necessary for PLA2 inhibition (Fig.…”

Section: Serotonin Release Assaymentioning

confidence: 99%

A requirement for membrane-associated phospholipase A2 in platelet cytotoxicity activated by receptors for immunoglobulin G and complement.

Symer

Paznekas

Shin

1993

The Journal of Experimental Medicine

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SunliitlsryPlatelets are potent antibody-and complement-dependent cytotoxic effector cells. We showed previously that a single platelet can lyse a target cell sensitized with immunoglobulin G (IgG) and complement components up to C3 (C,,o3b denotes the target cell-bound fragment of complement up to C3; the precise nature of the bound C3 fragment has not been established), and that the complete cytotoxic system capable of specific recognition and lysis resides in platelet membranes. To define the components of platelet membranes required for cytotoxicity, a set of inhibitors of phospholipase A2 (PLA2) that act by different chemical mechanisms was tested. The lytic reaction is blocked at appropriate concentrations of bromophenacylbromide, mepacrine, and manoalide. When platelets are treated with bromophenacylbromide, inhibition of cytolytic activity and that of PLA2 enzymatic activity occur in parallel. Platelets release arachidonate when incubated with target cells bearing IgG and C~3b, confirming that FcyR and complement receptor trigger both PLA2 action and efficient lysis. Inhibition by thimerosal of a reverse reaction, i.e., reacylation catalyzed by acyltransferase, causes increased target cell lysis, presumably by increasing the products of PLA2 action. Platelet cytotoxicity is increased when platelets are pretreated with some products of PLA2: exogenous lysophospholipids and not free arachidonic acid increase cytotoxicity. Electron microscopy suggests that platelets and target ceils may fuse, possibly as a result of the formation of lysophospholipids which are well-known membrane fusogens. Fixation with paraformaldehyde does not affect platelet cytotoxicity, suggesting that the complete cytotoxic system resides as a preformed complex in platelet membranes. The results indicate that platelet membrane-associated PLAz, together with receptors for Fc and complement, are required for platelet cytotoxicity. lthough small in size and lacking nuclei, platelets are potent cytotoxic effector cells present in numbers and total surface area that are vast in comparison with other bloodborne immune effectors (1, 2). Both mouse and human platelets bear receptors for the constant domains of IgG molecules (Fc3'R) and CR (3-6). Platelets are antibody-dependent tumoricidal effectors of the immune system in vivo (7-9). They also have been shown to lyse IgE-coated schistosomulae (10) and Brugia malayi microfilariae (11). In the absence of specific antibody, platelets can lyse Toxoptasma gondii (12) and tumor cells (13) in vitro. In these antibody-independent processes, the activation of phospholipase A2 (PLA2) 1 and the involvement of arachidonic acid metabolites have been implicated.

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Manoalide, a natural sesterterpenoid that inhibits calcium channels.

Cited by 60 publications

References 19 publications

Signal transduction by epidermal growth factor occurs through the subclass of high affinity receptors.

Signal transduction by epidermal growth factor occurs through the subclass of high affinity receptors.

Mechanism of cAMP-induced Ca2+ influx in Dictyostelium: role of phospholipase A2

A requirement for membrane-associated phospholipase A2 in platelet cytotoxicity activated by receptors for immunoglobulin G and complement.

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