Differential effects of trifluoperazine on arachidonate liberation, secretion and myosin phosphorylation in intact platelets

Holmsen, Holm; Daniel, James L.; Dangelmaier, Carol; Molish, Ilean R.; Rigmaiden, Marilyn; Smith, J B

doi:10.1016/0049-3848(84)90298-6

Cited by 30 publications

(9 citation statements)

References 24 publications

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“…Concentrations of phenothiazines around 40–50 µM, similar to the concentration of TDZ applied here, have been demonstrated to permeabilize the cytoplasmic membrane of human platelets to small solutes such as adenine nucleotides [48], [49]. To examine if a similar phenomenon takes place when S. aureus is treated with TDZ or DCX, cells were stained with the DNA stain propidium iodide (PI) and visualized by fluorescence microscopy.…”

Section: Resultsmentioning

confidence: 92%

Thioridazine Induces Major Changes in Global Gene Expression and Cell Wall Composition in Methicillin-Resistant Staphylococcus aureus USA300

et al. 2013

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Subinhibitory concentrations of the neuroleptic drug thioridazine (TDZ) are well-known to enhance the killing of methicillin-resistant Staphylococcus aureus (MRSA) by β-lactam antibiotics, however, the mechanism underlying the synergy between TDZ and β-lactams is not fully understood. In the present study, we have examined the effect of a subinhibitory concentration of TDZ on antimicrobial resistance, the global transcriptome, and the cell wall composition of MRSA USA300. We show that TDZ is able to sensitize the bacteria to several classes of antimicrobials targeting the late stages of peptidoglycan (PGN) synthesis. Furthermore, our microarray analysis demonstrates that TDZ modulates the expression of genes encoding membrane and surface proteins, transporters, and enzymes involved in amino acid biosynthesis. Interestingly, resemblance between the transcriptional profile of TDZ treatment and the transcriptomic response of S. aureus to known inhibitors of cell wall synthesis suggests that TDZ disturbs PGN biosynthesis at a stage that precedes transpeptidation by penicillin-binding proteins (PBPs). In support of this notion, dramatic changes in the muropeptide profile of USA300 were observed following growth in the presence of TDZ, indicating that TDZ can interfere with the formation of the pentaglycine branches. Strikingly, the addition of glycine to the growth medium relieved the effect of TDZ on the muropeptide profile. Furthermore, exogenous glycine offered a modest protective effect against TDZ-induced β-lactam sensitivity. We propose that TDZ exposure leads to a shortage of intracellular amino acids, including glycine, which is required for the production of normal PGN precursors with pentaglycine branches, the correct substrate of S. aureus PBPs. Collectively, this work demonstrates that TDZ has a major impact on the cell wall biosynthesis pathway in S. aureus and provides new insights into how MRSA may be sensitized towards β-lactam antibiotics.

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Section: Resultsmentioning

confidence: 92%

Thioridazine Induces Major Changes in Global Gene Expression and Cell Wall Composition in Methicillin-Resistant Staphylococcus aureus USA300

et al. 2013

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“…This is because the enzyme, which catalyzes the phosphorylation of MLC, is not membrane associated. MLC kinase exists in the cytoplasm and it does not translocate to the platelet Scheme 1 Chemical structures of the drugs membrane following its activation, dissimilar to phospholipases [76]. It is important to mention that ZIP, PCP, CPZ, and NTP decreased the phosphorylation process significantly, while the remaining 12 drugs either decreased or increased it insignificantly.…”

Section: Discussionmentioning

confidence: 99%

An intercalation mechanism as a mode of action exerted by psychotropic drugs: results of altered phospholipid substrate availabilities in membranes?

et al. 2010

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Patients respond differently to psychotropic drugs, and this is currently a controversial theme among psychiatrists. The effects of 16 psychotropics on cell membrane parameters have been reported. These drugs belong to three major groups used in therapeutic psychiatry: antipsychotics, antidepressants, and anxiolytic/hypnotics. Human platelets, lacking dopamine (D 2 ) receptors (proposed targets of most psychotropics), have been used as a cell model. Here we discuss the effects of these drugs on three metabolic phenomena and also results from Langmuir experiments. Diazepam, in contrast to the remaining drugs, had negligible effects on metabolic phenomena and had no effects in Langmuir experiments. Psychotropic drugs may work through intercalation in membrane phospholipids. It is possible that the fluidity of membranes, rich in essential fatty acids, the content being influenced by diet, could be a contributing factor to the action of psychotropics. This might in turn explain the observed major differences in therapeutic response among patients.

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“…The adenine nucleotides labelled with t32P]Pi in these experiments are exclusively present in the extragranular compartment [25], and their extracellular appearance is a measure of cell lysis [26][27][28]. Therefore 0.5 ml aliquots of 32P-labelled platelets were incubated with different concentrations ofpropranolol for 3 min.…”

Section: Study Of Platelet Lysismentioning

confidence: 99%

“…Propranolol is a cationic amphiphilic molecule that may have many properties in common with phenothiazines. The latter compounds permeabilize platelet membrane at concentrations above 40 ,uM, causing leakage of low-molecular-mass substances (ATP, glycolytic intermediates) but not lactate dehydrogenase from the cytoplasm [26][27][28]. Propranolol is known to induce physical changes in the platelet membrane [12].…”

Section: Propranolol Does Not Permeabilize Platelet Membrane Under Thmentioning

confidence: 99%

Effect of propranolol on platelet signal transduction

Dash

Rao

1995

Biochemical Journal

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Propranolol inhibits platelet secondary aggregation and secretion by mechanisms unrelated to its beta-adrenergic-blocking activity. We previously reported that a major effect of the drug is perturbation of the physical microenvironment of the human platelet membrane. To explore further the molecular mechanisms underlying propranolol-mediated platelet inhibition, we studied protein kinase C activity, estimated from the phosphorylation of the substrate protein pleckstrin, in propranolol-treated human platelets. The drug inhibited activation of the enzyme in thrombin-stimulated platelets but not in platelets stimulated with phorbol esters, indicating that its site of action might be upstream of protein kinase C. It also inhibited the activity of phospholipase C, determined from the extent of generation of inositol phosphates and phosphatidic acid, in platelets stimulated with thrombin as well as the non-hydrolysable GTP analogue guanosine 5'-[beta, gamma-imido]triphosphate in a dose-dependent manner. These data suggest that propranolol inhibits signal transduction in thrombin-stimulated platelets by interacting at the level of phospholipase C and exclude interaction of the drug with the downstream effector enzyme protein kinase C.

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Differential effects of trifluoperazine on arachidonate liberation, secretion and myosin phosphorylation in intact platelets

Cited by 30 publications

References 24 publications

Thioridazine Induces Major Changes in Global Gene Expression and Cell Wall Composition in Methicillin-Resistant Staphylococcus aureus USA300

Thioridazine Induces Major Changes in Global Gene Expression and Cell Wall Composition in Methicillin-Resistant Staphylococcus aureus USA300

An intercalation mechanism as a mode of action exerted by psychotropic drugs: results of altered phospholipid substrate availabilities in membranes?

Effect of propranolol on platelet signal transduction

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