Inhibition of Receptor Signaling to Phospholipase D by Clostridium difficile Toxin B

Schmidt, Martina; Rümenapp, Ulrich; Bienek, Christine; Keller, Jutta; Eichel‐Streiber, Christoph von; Jakobs, Karl H.

doi:10.1074/jbc.271.5.2422

Cited by 102 publications

(94 citation statements)

References 23 publications

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“…The linkage of PKC to the PLD signal transduction pathway may depend on the tissue and the stage of development studied (Briscoe et al, 1995;Exton, 1997;Klein et al, 1997;Schmidt et al, 1996). Additionally, it has been reported that PKC activation of PLD may occur by ATP independent mechanism (Conricode et al, 1992;Singer et al, 1996), and this mechanism would not be inhibited by the bisindolemalemide family of PKC inhibitors since their action is due to a competitive inhibition of the ATP binding site (Gordge & Ryves, 1994).…”

Section: Discussionmentioning

confidence: 99%

Activation of phospholipase D by metabotropic glutamate receptor agonists in rat cerebrocortical synaptosomes

Shinomura

Río

Breen

et al. 2000

British J Pharmacology

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1 The pharmacological pro®le of metabotropic glutamate receptor (mGluR) activation of phospholipase D (PLD), and the associated signalling pathways, were examined in rat cerebrocortical synaptosomes. The assay was conducted using a transphosphatidylation reaction in synaptosomes which were pre-labelled with either [ 3 H]-arachidonic acid or [ 32 P]-orthophosphate. 2 The mGluR agonists (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) and (RS)-3,5-dihydroxyphenylglycine (DHPG), both activated PLD, while phorbol 12,13-dibutyrate (PDBu) treatment caused receptor-independent activation of PLD and had an additive e ect on 1S,3R-ACPD induced PLD activity. 3 A protein kinase C (PKC) inhibitor, GF109203X, failed to antagonize mGluR receptor-coupled PLD activity. We could not detect any increase in the products of PI (phosphoinositide)-speci®c phospholipase C (PI-PLC), inositol(1,4,5)trisphosphate or diacylglycerol, by 1S, 3R-ACPD at 15 s. However, diacylglycerol increased monophasically in response to mGluR agonists and remained elevated for at least 15 min. Phosphatidic acid phosphohydrolase (PAP) activity, which converts PA to DAG, was present in the synaptosomes. 4 These data suggest that, in rat cerebrocortical synaptosomes, the 1S,3R-ACPD-sensitive mGluR is coupled to PLD through a mechanism that is independent of both PKC and PI-PLC.

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Section: Discussionmentioning

confidence: 99%

Activation of phospholipase D by metabotropic glutamate receptor agonists in rat cerebrocortical synaptosomes

Shinomura

Río

Breen

et al. 2000

British J Pharmacology

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“…This desensitization is apparently not a result of the loss of cell-surface receptors, but reflects a rapid and sustained uncoupling of the receptors from the activation of PLD. Second, it has been shown that addition of the phorbol ester PMA induces a pronounced stimulation of PLD activity in m3-HEK cells (40,41) as well as in many other mammalian cells (42,43). Examination of the published data indicate that 0.1 M PMA increased PLD activity to levels ϳ4-fold higher than those seen with a maximal concentration of carbachol (40).…”

Section: Arachidonate-mediated Ca 2ϩ Entry In Hek293 Cellsmentioning

confidence: 99%

Muscarinic Receptor Activation of Arachidonate-mediated Ca2+ Entry in HEK293 Cells Is Independent of Phospholipase C

Shuttleworth

Thompson

1998

Journal of Biological Chemistry

101

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Receptor] i oscillations.Calcium signaling in non-excitable cells is composed of two components: a release of calcium from intracellular stores and an increased entry of calcium from the extracellular medium. The role of inositol 1,4,5-trisphosphate (InsP 3 ), 1 generated as a result of the receptor activation of phospholipase C, in the release of calcium from specific intracellular stores is well established, but the nature of the calcium entry pathway and its regulation is far from clear. To date, discussion of such calcium entry has generally focused on the so-called "capacitative model," in which calcium entry is activated as a direct consequence of the emptying of the intracellular calcium stores and is independent of how this emptying is actually achieved (1, 2). The precise nature of the mechanism for the activation of capacitative entry is, as yet, unclear, but it may involve the release and/or generation of a diffusible signaling molecule within the cell that activates the plasma membrane channels ("store-operated channels") responsible for calcium entry. Alternatively, a more direct molecular coupling between the stores and the plasma membrane channels may occur (3). Although such capacitative entry can be clearly demonstrated in a wide variety of different cells, it is far from certain that such a mechanism is the only one involved in the increase in calcium entry in non-excitable cells following receptor activation (4, 5). For example, many cells show an oscillatory [Ca 2ϩ ] i signal when stimulated at low agonist concentrations (6, 7), and such signals are associated with an enhanced entry of Ca 2ϩ . However, evidence indicates that the activation of capacitative Ca 2ϩ entry generally requires significantly higher levels of agonist-generated InsP 3 than does the release of Ca 2ϩ from the bulk of the agonist-sensitive internal stores (i.e. at low concentrations of InsP 3 , substantial release of Ca 2ϩ from agonistsensitive stores can occur without any activation of capacitative entry) (8 -10). Consequently, it is far from clear that the transitory (and/or incomplete) nature of calcium store depletion during [Ca 2ϩ ] i oscillations would provide an adequate or appropriate signal for the activation of calcium entry via a capacitative mechanism. Such considerations led us previously to investigate the nature of receptor-activated increases in Ca 2ϩ entry during [Ca 2ϩ ] i oscillations in cells from the exocrine avian nasal gland. In these studies, we showed that such Ca 2ϩ entry was non-capacitative in nature (11) and appeared to involve a novel arachidonate-activated pathway (12).In the experiments reported here, we extend our earlier findings to another, more widely used and functionally less highly specialized cell type, namely HEK293 cells. The specific cell line chosen had been stably transfected with the human m3 muscarinic receptor (m3-mAChR), thereby avoiding possible complications resulting from the presence of multiple muscarinic receptor subtypes. Using this cell line, we were able to s...

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“…Receptor regulation of PLD activity in human embryonic kidney (HEK)-293 cells, stably expressing the human M $ muscarinic acetylcholine receptor (mAChR) subtype, involves both ARF and Rho proteins [22,23]. Studies on the mechanisms of PLD inhibition by Clostridium difficile toxin B and C. botulinum C3 exoenzyme, which inactivate Rho family GTPases [24], indicated that these toxins decrease the cellular level of PtdIns(4,5)P # [25,26].…”

Section: Introductionmentioning

confidence: 99%

Tyrosine-phosphorylation-dependent and Rho-protein-mediated control of cellular phosphatidylinositol 4,5-bisphosphate levels

Rümenapp

Schmidt

Olesch

et al. 1998

Biochemical Journal

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The polyphosphoinositide PtdIns(4,5)P # , best known as a substrate for phospholipase C isozymes, has recently been recognized to be involved in a variety of other cellular processes. The aim of this study was to examine whether the cellular levels of this versatile phospholipid are controlled by tyrosine phosphorylation. The studies were performed in human embryonic kidney (HEK)-293 cells stably expressing the M $ muscarinic acetylcholine receptor. Inhibition of tyrosine phosphatases by pervanadate induced an up-to-approx.-2.5-fold increase in the total cellular level of PtdIns(4,5)P # , which was both time-and concentration-dependent. In contrast, the tyrosine kinase inhibitors, genistein and tyrphostin 23, caused a rapid and specific fall in the cellular PtdIns(4,5)P # level and prevented the stimulatory effect of pervanadate on PtdIns(4,5)P # formation. Inactivation of Rho proteins by Clostridium difficile toxin B caused a similar fall in

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Inhibition of Receptor Signaling to Phospholipase D by Clostridium difficile Toxin B

Cited by 102 publications

References 23 publications

Activation of phospholipase D by metabotropic glutamate receptor agonists in rat cerebrocortical synaptosomes

Activation of phospholipase D by metabotropic glutamate receptor agonists in rat cerebrocortical synaptosomes

Muscarinic Receptor Activation of Arachidonate-mediated Ca2+ Entry in HEK293 Cells Is Independent of Phospholipase C

Tyrosine-phosphorylation-dependent and Rho-protein-mediated control of cellular phosphatidylinositol 4,5-bisphosphate levels

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