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PubMedDate not supplied

Age and growth-related changes in cyclopiazonic acid-potentiated lipophilic cation accumulation by cultured cells and binding to freeze-thaw lysed cells.

In a previous study (1) we demonstrated that increased tetraphenylphosphonium (TPP) uptake by renal epithelial cells (LLC-PK1) exposed to the fungal metabolite cyclopiazonic acid (CPA) was not a result of hyperpolarization across the plasma membrane even though CPA-potentiated TPP uptake could be totally inhibited by the depolarizing agent carbonylcyanide-m-chlorophenylhydrazone (CCCP). We now demonstrate that CPA potentiates TPP accumulation by proliferating skeletal muscle (L6) and LLC-PK1 cells but not by nonproliferating primary rat hepatocytes. In LLC-PK1 cells, CPA-potentiated TPP accumulation is observed in cells at all ages. In L6 cells, CPA-potentiated TPP accumulation is maximal soon after subculturing, and as the cells age they become less sensitive to CPA until TPP accumulation by CPA-treated cells approaches that of untreated cells. The temporal change in sensitivity of L6 cells to CPA may be related to biochemical and/or metabolic changes which occur as the cells age in culture. Hepatocytes, LLC-PK1 cells, and L6 cells permeabilized by freeze-thaw lysis, all exhibit CPA-potentiated TPP partitioning, even in the presence of CCCP. This result indicates that both TPP and CPA must have access to the intracellular space in order for potentiated TPP partitioning to be observed. We hypothesize that the site of interaction between CPA and TPP is intracellular and probably associated with the cytoplasmic side of the plasma membrane and possibly the mitochondria.

Animals↗
PubMed2006

Ab initio QM/MM dynamics of H3O+ in water.

A molecular dynamics (MD) simulation based on a combined ab initio quantum mechanics/molecular mechanics (QM/MM) method has been performed to investigate the solvation structure and dynamics of H3O+ in water. The QM region is a sphere around the central H3O+ ion, and contains about 6-8 water molecules. It is treated at the Hartree-Fock (HF) level, while the rest of the system is described by means of classical pair potentials. The Eigen complex (H9O4+) is found to be the most prevalent species in the aqueous solution, partly due to the selection scheme of the center of the QM region. The QM/MM results show that the Eigen complex frequently converts back and forth into the Zundel (H5O2+) structure. Besides the three nearest-neighbor water molecules directly hydrogen-bonded to H3O+, other neighbor waters, such as a fourth water molecule which interacts preferentially with the oxygen atom of the hydronium ion, are found occasionally near the ion. Analyses of the water exchange processes and the mean residence times of water molecules in the ion's hydration shell indicate that such next-nearest neighbor water molecules participate in the rearrangement of the hydrogen bond network during fluctuative formation of the Zundel ion and, thus, contribute to the Grotthuss transport of the proton.

Computer Simulation↗
PubMed1983

Comparison of indirect probes of membrane potential utilized in studies of human neutrophils.

Four indirect probes of membrane potential, triphenylmethylphosphonium ion (TPMP+), 3,3'dipentyloxacarbocyanine [di-O-C5(3)], 3,3'dipentylindocarbocyanine [di-I-C5(3)], and 3,3'dipropylthiodicarbocyanine [di-S-C3(5)] have been used to study neutrophil (PMN) activation. The data extend previous studies indicating that the cyanine dye di-S-C3(5) not only exhibits a different fluorescence response mechanism from di-O-C5(3) [and di-I-C5(3)] but also that the fluorescence of di-S-C3(5) is destroyed by reactive oxygen products produced by neutrophils following stimulation. When these aspects of the probes are taken into account, the interpretations of the results using all three cyanine dyes are identical. Studies with the isotope TPMP+ indicate that long incubations are necessary for PMN to fully equilibrate during which time the PMNs depolarize. Use of TPB-, to shorten the TPMP+ equilibration time, produces results identical with those obtained using the cyanine dyes. The cyanine dyes and TPMP+/TPB- are toxic to neutrophil functions although they do not cause cell death. Toxicity can be avoided by using low concentrations of di-O-C5(3) and di-I-C5(3) but cannot be avoided with di-S-C3(5) or TPMP+/TPB-. Using di-O-C5(3) with the fluorescence-activated cell sorter, we demonstrate that heterogeneity of neutrophil responsiveness confuses the interpretation of studies characterizing the ionic basis of the fluorescence responses stimulated by certain stimuli. We conclude that some of the discrepancies currently reported in the literature using these probes are not due to inherent differences in the ability of the different probes to monitor the same event (i.e., PMN membrane potential) but instead are due to failure to correct for probe-specific problems or response heterogeneity.

Carbocyanines↗
PubMed1984

Relationship of muscle growth in vitro to sodium pump activity and transmembrane potential.

Serum stimulates embryonic avian skeletal muscle growth in vitro and the growth-related processes of amino acid transport and protein synthesis. Serum also stimulates myotube Na pump activity (measured as ouabain-sensitive rubidium-86 uptake) for at least 2 h after serum addition. Serum-stimulated growth depends on this Na pump activity since ouabain added at the same time as serum totally inhibits the growth responses. The relationship of myotube growth, Na pump activity, and transmembrane potential was studied to determine whether serum-stimulated Na pump activation and growth are coupled by long-term membrane hyperpolarization. When myotube amino acid transport and protein synthesis are prestimulated by serum, ouabain was found to have little inhibitory effect, indicating that the already stimulated growth-related processes are not tightly coupled to continued Na pump activity. Serum-stimulated protein synthesis is tightly coupled to Na pump activity, but only during the first 5-10 min after serum addition. When myotube transmembrane potentials were measured using the lipophilic cation tetraphenylphosphonium, serum at concentrations that stimulate myotube growth and Na pump activity was found to have little effect on the cell's transmembrane potential. Furthermore, partial depolarization of the myotubes with 12- to 55-mM extracellular potassium does not prevent serum stimulation of myotube growth. Monensin was found to hyperpolarize the myotubes, but causes myotube atrophy. These results indicate that although Na pump activity is associated with initiation of serum-stimulated myotube growth, continued Na pump activity is not essential, and there is little relationship between myotube growth and the myotube's transmembrane potential.

Amino Acids↗
PubMed1986

Plasma membrane potential of murine erythroleukemia cells: approach to measurement and evidence for cell-density dependence.

The plasmamembrane potential (delta psi p) of murine erythroleukemia (MEL) cells has been determined by measuring the distribution of the lipophilic cation tetraphenylphosphonium (TPP+) across the plasmamembrane. TPP+ accumulation within the cells (experimental accumulation ratio, AR exp) was measured by adding 2 microM TPP+ directly to the culture flasks, avoiding any other perturbation of the experimental system. The mitochondrial contribution to AR exp, evaluated by adding carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) or 2,4-dinitrophenol (DNP), was apparently negligible in standard cultures, AR exp being substantially the same in either the absence or presence of these uncouplers. However, the addition of oligomycin produced a strong AR exp enhancement, which was abolished by FCCP, suggesting that MEL cell mitochondria are in state 3. The aspecific TPP+ binding was estimated by a new mathematical approach worked out to fit AR exp values measured in the presence of valinomycin at various extracellular K+ concentrations and plotted against the ratio of intracellular to extracellular K+ concentration ([K+]i/[K+]e). This binding was found to be close to zero in MEL cells. By applying the Nernst equation directly to AR exp values, delta psi p of these cells was then measured; this potential varying from -65 mV to -16 mV (inside negative) is inversely related to the cell density on the culture surface on which the cells sediment (cells/cm2; CD). The dependence of delta psi p on CD is practically eliminated by valinomycin and appears to be related to a cell interaction with the culture surface of the flasks, suggesting that in the immediate environment of MEL cells one or more factors are produced that modulate the K+ plasma membrane permeability (PK).

Animals↗
PubMed1990

Ionic regulation of the plasma membrane potential of rainbow trout (Salmo gairdneri) spermatozoa: role in the initiation of sperm motility.

The ionic dependence of the trout sperm plasma membrane potential was analysed by measuring the accumulation of the lipophilic ions 3H-tetraphenylphosphonium (TPP) and 14C-thiocyanate (SCN) following dilution in artificial media isotonic to the seminal fluid. Our data showed that the trout sperm plasma membrane has a mixed conductance: the plasma membrane potential is sensitive upon the transmembrane gradients of K+, Na+, and H+. This potential is negative (less than -40 mV) in a 125 mM choline chloride media (ChM) at pH 8.5. Replacement of choline by sodium has a small depolarizing effect. The membrane potential is about -15 mV in a 125 mM potassium chloride and falls near zero mV only if valinomycin is added. In ChM changing the external pH (pHe) greatly affects the membrane potential: its value rises from less than -40 mV at pHe 9.0 to -17 mV at pHe 5.0. This pH effect is observed also in presence of sodium or potassium. A decrease in the transmembrane proton gradient produced by increasing internal pH without changing pHe induces also a depolarisation of the plasma membrane. In the different media in which trout sperm remain immotile after dilution (media with [K+] greater than 20-40 mM or a pH less than 7.5) the plasma membrane is more depolarized than in media allowing motility, suggesting a relationship between the state of membrane polarization and the intracellular effectors of the axonemal movement.

Animals↗
PubMed1990

Effects of hyperthermia on the membrane potential and Na+ transport of V79 fibroblasts.

The effects of hyperthermia (41-43 degrees C) on the membrane potential (calculated from the transmembrane distribution of [3H]tetraphenylphosphonium) and Na+ transport of Chinese hamster V79 fibroblasts were studied. At 41 degrees C, hyperthermia induced a membrane hyperpolarization of log phase cells (5 to 26 mV) that was reversible upon returning to 37 degrees C. The hyperpolarization was inhibited 50% by 1 mM ouabain or 0.25 mM amiloride, an inhibitor of Na+:H+ exchange. Shifting temperature to 41 degrees C increased ouabain-sensitive Rb+ uptake indicating activation of the electrogenic Na+ pump. At 43 degrees C for 60 min, the membrane potential of log phase cells depolarized (20-35 mV). Parallel studies demonstrated enhanced Na+ uptake at 41 degrees C only in the presence of ouabain. At 43 degrees C, Na+ uptake was increased relative to controls with or without ouabain present. At both 41 and 43 degrees C, 0.25 mM amiloride inhibited heat-stimulated Na+ uptake. Na+ efflux was enhanced at 41 degrees C in a process inhibited by ouabain. Thus, one consequence of heat treatment at 41 degrees C is activation of Na+:H+ exchange with the resultant increase in cytosolic [Na+] activating the electrogenic Na+ pump. At temperatures greater than or equal to 43 degrees C, the Na+ pump is inhibited.

Amiloride↗
PubMed2001

Regulation of angiotensin II-stimulated osteopontin expression in cardiac microvascular endothelial cells: role of p42/44 mitogen-activated protein kinase and reactive oxygen species.

Using spontaneously hypertensive and aortic banded rats, we have shown that expression of myocardial osteopontin, an extracellular matrix protein, coincides with the development of heart failure and is inhibited by captopril, suggesting a role for angiotensin II (ANG II). This study tested whether ANG II induces osteopontin expression in adult rat ventricular myocytes and cardiac microvascular endothelial cells (CMEC), and if so, whether induction is mediated via activation of mitogen-activated protein kinases (p42/44 MAPK) and involves reactive oxygen species (ROS). ANG II (1 microM, 16 h) increased osteopontin expression (fold increase 3.3+/-0.34, n = 12, P < 0.01) in CMEC as measured by northern analysis, but not in ARVM. ANG II stimulated osteopontin expression in CMEC in a time- (within 4 h) and concentration-dependent manner, which was prevented by the AT1 receptor antagonist, losartan. ANG II elicited robust phosphorylation of p42/44 MAPK as measured using phospho-specific antibodies, and increased superoxide production as measured by cytochrome c reduction and lucigenin chemiluminescence assays. These effects were blocked by diphenylene iodonium (DPI), an inhibitor of the flavoprotein component of NAD(P)H oxidase. PD98059, an inhibitor of p42/44 MAPK pathway, and DPI each inhibited ANG II-stimulated osteopontin expression. Northern blot analysis showed basal expression of p22phox, a critical component of NADH/NADPH oxidase system, which was increased 40-60% by exposure to ANG II. These results suggest that p42/44 MAPK is a critical component of the ROS-sensitive signaling pathways activated by ANG II in CMEC and plays a key role in the regulation of osteopontin gene expression. Published 2001 Wiley-Liss, Inc.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed1989

Regulation of phagolysosome pH in bovine and human neutrophils: the role of NADPH oxidase activity and an Na+/H+ antiporter.

Fluorescein-labelled Staphylococcus aureus were used to follow changes in phagolysosome (PL) pH of bovine and human neutrophils following phagocytosis. Under aerobic conditions there was an alkalinisation of the PL followed by a slow decline. Under anaerobic conditions no alkalinisation of the PL was seen, and pharmacological inhibition of the NADPH oxidase with diphenyleneiodonium (DPI) resulted in a rapid acidification of the PL following phagocytosis. The inclusion of amiloride, an inhibitor of Na+/H+ antiporter activity, produced a more rapid alkalinisation phase following phagocytosis under aerobic conditions and reduced, but did not abolish, the acidification phases seen under anaerobic conditions or following treatment of neutrophils with DPI. The results suggest that PL pH is influenced by NADPH oxidase activity and to a lesser extent by a Na+/H+ antiporter. The antibacterial effectiveness of neutrophil granule proteins may be affected under conditions that influence the functioning of these two systems.

Amiloride↗
PubMed1996

Microbial killing by human neutrophil cytokineplasts: similar suppressive effects of reversible and irreversible inhibitors of nitric oxide synthase.

Employing anucleate, granule-poor, motile fragments from human blood neutrophils (cytokineplasts; CKP), we previously provided evidence for a new staphylococcal killing pathway for human neutrophils involving reactive nitrogen intermediates: the NO synthase inhibitor N(omega)-monomethyl-L-arginine (NMMA), an analogue of L-arginine (L-Arg), substantially decreased the killing capacity of CKP for Staphylococcus aureus (Staph), an effect reversible by excess L-Arg but not D-Arg. We have extended these findings to two irreversible NO synthase inhibitors: the first, N-iminoethyl-L-ornithine (L-NIO), is an L-Arg analogue; the other, diphenyleneiodonium (DPI), is not. After 60 min of incubation with bacteria, despite having taken up somewhat fewer staphylococci than did controls, cytoplasts treated with NO synthase inhibitors had many more live, CKP-associated bacteria: for NMMA, 6.9 times more (40.0% of the inoculum vs. 5.8%; n = 8, P = 0.003); for L-NIO, 3.6 times more (25.5 vs. 7%; n = 4, P = 0.004); for DPI, 5.8 times more (37.4 vs. 6.4%; n = 7, P = 0.002). Results were similar after only 20 min of incubation. In two experiments in which the Gram-negative bacterium, Serratia marcescens, was employed instead of Staph, the results were again similar. In contrast, killing of either bacterium by intact neutrophils (PMN) was not inhibited by NMMA, by L-NIO, or by DPI, a failure most likely attributable to their granule content. The irreversible inhibitors of NO synthase will be especially useful in analyzing particular effects on CKP employed in multicellular systems.

Arginine↗
PubMed1997

Chemotaxis by human neutrophils and their cytokineplasts treated with inhibitors of nitric oxide synthase: no suppression of orientation or trajectory.

Inhibitors of nitric oxide (NO) synthase are reported to inhibit both the adherence of polymorphonuclear leukocytes (PMN) to substrate and chemotaxis (directed locomotion) of PMN as determined in Boyden chamber assays. In the current study, we examined both human blood PMN and granule-poor motile cytoplasts derived from them (cytokineplasts, CKP), under direct microscopic observation with concomitant time-lapse video recording, for their ability to respond chemotactically to an erythrocyte destroyed by laser microirradiation. In this system we can observe directly and continuously the orientation and trajectory of PMN before, during, and after establishment of a chemotactic gradient. For both PMN and CKP we employed three different inhibitors of NO synthase (N(omega)-methyl-L-arginine, N-iminoethyl-L-ornithine, and diphenyleneiodonium) in at least twice the concentrations employed to inhibit chemotaxis of PMN in Boyden chambers or killing of bacteria in CKP. Although small differences in adhesion might not have been appreciated, treated PMN and CKP were each indistinguishable from untreated controls in their ability to orient in a newly created chemotactic gradient and in their trajectories toward the chemotactic target.

Arginine↗
PubMed1998

Impairment of human neutrophil oxidative burst by polychlorinated biphenyls: inhibition of superoxide dismutase activity.

We report evidence of a novel mechanism by which polychlorinated biphenyls might act as potent inducers of inflammation. Aroclor 1242 (A1242), a polychlorinated biphenyl mixture, and 2,2',4,4'-tetrachlorobiphenyl (PCB47), a constituent of A1242 that produces the same patterns of effects, impaired the oxidative burst of human neutrophils by inhibiting the antioxidant enzyme superoxide dismutase, which converts O2- to H2O2. Pre-incubation of neutrophils with A1242 or PCB47 before stimulation with phorbol 12-myristate 13-acetate heightened the respiratory burst, producing a significant increase in intracellular O2- production along with a significant decrease in H2O2 production compared with unexposed agonist-stimulated neutrophils. This was also evident in a physiologically relevant situation in which neutrophils pre-incubated with A1242 were subsequently stimulated with a combination of N-formyl-L-methionyl-L-leucyl-L-phenylalanine and tumor necrosis factor-alpha. Incubation of bovine copper-zinc superoxide dismutase (EC 1.15.1.1) with A1242 or PCB47 in a cell-free system reversed the enzyme-mediated inhibition of 6-hydroxydopamine autoxidation, indicating that polychlorinated biphenyls inhibited superoxide dismutase activity. Low superoxide dismutase activity in neutrophils leads to imbalances between production of free radicals and antioxidant defense mechanisms, which can in turn induce tissue damage and hasten the onset of neutrophil apoptosis.

Adult↗
PubMed2006

Enhanced detection of sulfo-peptides as onium salts in matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

A new two-component system, consisting of a matrix and an onium salt as comatrix, is described for detection of sulfo-peptides in the positive mode by matrix-assisted desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS). Binary iodonium salts were superior to quaternary phosphonium salts in terms of suppression of desulfation and salt formation with the carboxyl group. Of the iodonium salts examined, bis(4-tert-butylphenyl)iodonium (BTI) hexafluorophosphate and bromide were most effective in giving intensive molecular ion signals in the form of [M(BTI)+BTI](+). The conditions optimized for O-sulfated tyrosine-containing peptides could be applicable for O-sulfated serine- and threonine-containing peptides. In the case of a phospho-peptide, a molecular ion appeared more intensively as a proton adduct than as a BTI adduct.

Cholecystokinin↗
PubMed1993

Inorganic pyrophosphate gives a membrane potential in yeast mitochondria, as measured with the permeant cation tetraphenylphosphonium.

Evidence for a membrane potential (delta psi) generating capacity of inorganic pyrophosphate (PPi) with inorganic pyrophosphatase in mitochondria from the yeast Saccharomyces cerevisiae is presented. Addition of PPi increases the accumulation of the permeant cation tetraphenylphosphonium (TTP+) in mitochondria, as measured with a TPP(+)-selective electrode or using [3H]TPP+. This accumulation is strongly inhibited by the uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) but not by oligomycin, whereas accumulation of TPP+ induced by ATP is strongly inhibited by both FCCP and oligomycin. The values of delta psi obtained upon addition of PPi were similar to those obtained when yeast mitochondria were energized by NADH or ATP. Energization of the wild type yeast mitochondria with ATP resulted in higher delta psi values than those achieved when PPi was hydrolyzed, whereas the effect of PPi was more pronounced in mitochondria from a pyrophosphatase (PPase) overproducing yeast strain. These results clearly indicate that PPi is significant as an energy donor and that the yeast mitochondrial PPase, the gene for which we have recently cloned and sequenced, may participate in energy transfer reactions.

Adenosine Triphosphate↗
PubMed1994

Mechanism of prostaglandin E2 release and increase in PGH2/PGE2 isomerase activity by PDGF: involvement of nitric oxide.

We examined the possibility that the platelet-derived growth factor-induced release of prostaglandin E2 and increase in prostaglandin H2 (PGH2)/prostaglandin E2 (PGE2) isomerase activity (EC 5.3.99.3) in NIH3T3 cells was mediated by nitric oxide. Addition of L-NG-nitroarginine methyl ester or diphenyleneiodonium chloride, potent nitric oxide synthase inhibitors, blocks platelet derived growth factor-induced release of prostaglandin E2, lowers basal prostaglandin E2 release, and also blocks the growth factor-induced increase in PGH2/PGE2 isomerase activity. Exogenous nitric oxide stimulates prostaglandin E2 release in NIH3T3 cells and this stimulation is blocked by hemoglobin. In contrast, exogenous nitric oxide failed to induce prostaglandin E2 release from pEJ/ras-transformed cells. The nitric oxide induction of PGH2/PGE2 isomerase activity and prostaglandin E2 release occurred within minutes in contrast to alterations in prostaglandin H synthase/cyclooxygenase. These findings link three different classes of messenger molecules (growth factors, nitric oxide, prostaglandins).

3T3 Cells↗
PubMed1994

Release of mitochondrial glutathione and calcium by a cyclosporin A-sensitive mechanism occurs without large amplitude swelling.

Treatment of isolated mitochondria with calcium and inorganic phosphate induces inner membrane permeability that is thought to be mediated through a non-selective, calcium-dependent pore. The inner membrane permeability results in the rapid efflux of small matrix solutes such as glutathione and calcium, loss of coupled functions, and large amplitude swelling. We have identified conditions of permeability transition without large amplitude swelling, a parameter often used to assess inner membrane permeability. The addition of either oligomycin, antimycin, or sulfide to incubation buffer containing calcium and inorganic phosphate abolished large-amplitude swelling of mitochondria but did not prevent inner membrane permeability as demonstrated by the release of mitochondrial glutathione and calcium. The release of both glutathione and calcium was inhibited by the addition of cyclosporin A, a potent inhibitor of permeability transition. Transmission electron microscopy analysis, combined with the glutathione and calcium release data, indicate that permeability transition can be observed in the absence of large-amplitude swelling. Permeability transition occurring both with and without large-amplitude swelling was accompanied by a collapse of the membrane potential. We conclude that cyclosporin A-sensitive permeability transition can occur without obvious morphological changes such as large-amplitude swelling. Monitoring the cyclosporin A-sensitive release of concentrated endogenous matrix solutes, such as GSH, may be a sensitive and useful indicator of permeability transition.

Animals↗