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PubMed1992

Valinomycin modifies phosphorescence quenching in cytochrome c oxidase.

The spectrum of resting cytochrome c oxidase is modulated by valinomycin addition, which induces a red shift of the Soret band. The enzyme is known both to fluoresce and phosphorescence, effects which can be modulated by certain protein reagents and quenchers. Valinomycin had little effect upon fluorescence at 335 nm, whether excited at 295 nm or 280 nm (tryptophans or both tryptophans and tyrosines, respectively). Phosphorescence at 445 nm was slightly enhanced upon the binding of valinomycin to the enzyme, suggesting a small conformational change accompanying the spectral shift of the heme groups. The quenching by nitrite of the phosphorescence excited at 260 nm, but not that excited at 295 nm, was diminished by valinomycin. This suggests that the valinomycin-induced conformational change may involve (i) a change in the accessibility of tyrosines to the quencher and/or (ii) a change in distribution of distances and/or orientations between populations of tyrosines and tryptophans.

Animals↗

PubMed1994

Combination of the electrogenic ionophores, valinomycin and CCCP, can lead to non-electrogenic K+/H+ exchange on bilayer lipid membranes.

The method of pH shift measuring by means of a pH microelectrode was applied to measure hydrogen ion fluxes across a planar bilayer lipid membrane (BLM) in the presence of the potassium ion ionophore, valinomycin, and a protonophore, carbonylcyanide m-chlorophenylhydrazone (CCCP), under conditions of the voltage clamp. The voltage dependence of the flux was determined to be in the range of +/- 150 mV under the conditions of both symmetrical KCl as well as a KCl gradient across the BLM. Surprisingly, at a clamped zero voltage on BLM a significant hydrogen ion flux was observed in the presence of a KCL gradient and both valinomycin and CCCP. This finding was interpreted as a result of induction of non-electrogenic K+/H+ exchange in the presence of valinomycin and CCCP, presumably through the formation of electrically neutral complexes of these two ionophores and K+ (H+) ions: valinomycin-K(+)-CCCP- and/or possibly valinomycin-CCCP(-)-H+.

Carbonyl Cyanide m-Chlorophenyl Hydrazone↗

PubMed2003

Iron and magnesium exchange via the low affinity iron transporter in rabbit erythroid cells-exchange rates and the action of valinomycin, diethylstilbestrol and protein kinase inhibitors.

Evidence was presented previously that rabbit erythroid cells possess a low-affinity Fe2+ transport system which operates via the Na+/Mg2+antiport [Biochim. Biophys. Acta 1282 (1996) 163]. This was investigated further by measurements of Mg2+ efflux as well as Fe2+ uptake by the cells and by examining the inhibitory effects of valinomycin, diethylstilbestrol (DES) and protein kinase inhibitors. Mg2+ efflux and Fe2+ uptake were measured using rabbit reticulocytes and mature erythrocytes incubated in isotonic KCl or NaCl solutions. Both processes were slower in mature cells than reticulocytes. Mg2+ efflux into KCl solution was much lower than into NaCl solution but was stimulated by addition of Fe2+ to the solution. The rate of Fe2+-stimulated Mg2+ efflux closely followed that of Fe2+ uptake in a one-to-one molar ratio. Valinomycin, DES and the protein kinase inhibitors all inhibited Fe2+ uptake from KCl solution. Valinomycin also inhibited Fe2+-stimulated Mg2+ efflux into KCl solution but markedly stimulated the efflux into NaCl. Maximal inhibition of Fe2+ uptake from KCl solution required the presence of K+, Rb+ or Cs+ ions with which valinomycin forms strong complexes. The results could not be explained on the basis of changes in cell membrane potential or cell volume. By contrast, the increase in Mg2+ efflux into NaCl solution produced by valinomycin was accompanied by cell shrinkage and production of a more negative membrane potential, either of which may be responsible for the effect. The inhibition produced by the protein kinase inhibitors indicate that phosphorylation of the transporter or an associated protein by protein tyrosine kinase is probably required to activate the transporter.

Animals↗

PubMed1976

Conformational studies of peptide cyclo-(D-Val-L-Pro-L-Val-D-Pro]3, a cation-binding analogue of valinomycin.

The solution conformation of cyclo-[D-Val-L-Pro-L-Val-D-Pro]3 (PV) and its alkali-metal ion complexes was investigated by proton nuclear magnetic resonance spectroscopy. It is concluded that the cation complexes of PV have S6 symmetry and are essentially isostructural with the K complex of valinomycin. In contrast to valinomycin, the Li- and Na-PV complexes are stable in methanol and have dissociation rate constants that are several orders of magnitude slower than the corresponding valinomycin complexes. Also in contrast to valinomycin, free PV exists in two different conformational states which interconvert at very slow rates (less than 1 s-1). One of these conformers has S6 symmetry and is structurally similar to that of the cation complexes. The other species, which has lower symmetry than S6, is the more stable conformer. Depending upon concentration and solvent polarity, the latter represents between 50 and 75% of the total mixture. It is proposed that PV may have a higher affinity for cations than valinomycin because of its higher potential energy in the uncomplexed state.

Cations, Monovalent↗

PubMed1974

Ionophore-mediated coupling between ion fluxes and amino acid absorption in mouse ascites-tumour cells. Restoration of the physiological gradients of methionine by valinomycin in the absence of adenosine triphosphate.

1. Preparations of mouse ascites-tumour cells depleted of ATP and Na(+) ions accumulated l-methionine, in the presence of cyanide and deoxyglucose, from a 1mm solution containing 80mequiv. of Na(+)/l and about 5mequiv. of K(+)/l. Valinomycin increased, from about 4 to 16, the maximum value of the ratio of the cellular to extracellular concentrations of methionine formed under these conditions without markedly affecting the distributions of Na(+) and of K(+). Similar observations were made with 2-aminoisobutyrate, glycine and l-leucine. Increasing the extracellular concentration of K(+) progressively decreased the accumulation of methionine in the presence of valinomycin. Over the physiological range of ionic gradients, the system behaved as though the absorption of methionine with Na(+) was closely coupled to the electrogenic efflux of K(+) through the ionophore. The process was insensitive to ouabain and so the sodium pump was probably not involved. 2. The amount of methionine accumulated during energy metabolism was similar to the optimal accumulation in the presence of valinomycin when ATP was lacking. It was also similarly affected by increasing the methionine concentration. 3. A mixture of nigericin and tetrachlorosalicylanilide mimicked the action of valinomycin. The anilide derivative inhibited the absorption of 2-aminoisobutyrate in the presence of valinomycin, but not in its absence. 4. Gramicidin inhibited methionine absorption and caused the preparations to absorb Na(+) and lose K(+). 5. The observations appear to verify the principle underlying the gradient hypothesis by showing that the tumour cells can efficiently couple the electrochemical gradient of Na(+) to the amino acid gradient.

Adenosine Triphosphate↗

PubMed2002

Permeability transition-independent release of mitochondrial cytochrome c induced by valinomycin.

To examine whether valinomycin induces a mitochondrial permeability transition (PT), we investigated its effects on mitochondrial functions under various conditions. The acceleration of mitochondrial respiration and swelling, induced by valinomycin, were found to be insensitive to inhibitors of the ordinary PT, indicating that valinomycin does not induce the ordinary PT. Results of experiments using mitochondria isolated from transgenic mice expressing human bcl-2 also supported this conclusion. Furthermore, evidence for induction of PT pores by valinomycin was not obtained by either electron microscopic analysis of mitochondrial configurations or by measurement of the permeability of the inner mitochondrial membrane by use of polyethylene glycol. However, valinomycin did induce a significant release of cytochrome c, and thus it may be a nice tool to study the processes of mitochondrial cytochrome c release.

Animals↗

PubMed1990

Streptomyces genes involved in biosynthesis of the peptide antibiotic valinomycin.

We have identified genes from Streptomyces levoris A-9 involved in the biosynthesis of the peptide antibiotic valinomycin. Two segments of chromosomal DNA were recovered from genomic libraries, constructed by using the low-copy-number plasmid pIJ922, by complementation of valinomycin-deficient (vlm) mutants of S. levoris A-9. One set of plasmids restored valinomycin production to only one mutant, that carrying vlm-1, whereas a second set of plasmids restored productivity to seven vlm mutants, those carrying vlm-2 through vlm-8. Additional complementation studies using subcloned restriction enzyme fragments showed that the vlm-1+ gene was contained within a 2.5-kilobase (kb) DNA region, whereas alleles vlm-2+ through vlm-8+ were contained in a 12-kb region, representing at least three genes. Physical mapping experiments based on the isolation of cosmid clones showed that the two vlm loci were 50 to 70 kb apart. Southern hybridization experiments demonstrated that the vlm-2+ gene cluster was highly conserved among other valinomycin-producing Streptomyces strains, whereas the vlm-1+ gene was ubiquitous among Streptomyces species tested. Increasing the copy number of the vlm-2+ gene cluster in S. levoris A-9 by the introduction of low-copy-number recombinant plasmids resulted in a concomitant increase in the level of valinomycin production.

Alleles↗

PubMed1978

Effects of valinomycin on Rb+ fluxes, ATP content and insulin release in pancreatic islets.

Valinomycin, 0.5-500 nM, was tested for its effects on pancreatic islets microdissected fron non-inbred ob/ob-mice. Valinomycin decreased the islet accumulation Rb+ and the content of ATP in a dose-dependent manner; efflux of Rb+ from pre-loaded islets was not noticeably changed. Rb+ accumulation and ATP content correlated markedly; on the model of linear regression, less than 10% of the change Rb+ accumulation in valinomycin-treated islets was statistically attributable to factors other than ATP. Valinomycin did not cause a prompt inhibition of glucose-stimulated insulin release that could reflect hyperpolarization due to increased K+ permeability. The following conclusions are drawn: 1) The plasma membranes of beta-cells resemble those of neurons in having such a high ion permeability as to be relatively little influenced by valinomycin; 2) Islet accumulation of Rb+ is due to a vectorial catalyst in theplasma membrane rather than to uptake by mitochondria; 3) Rb+ accumulation in islets is ATP-dependent.

Adenosine Triphosphate↗

PubMed1987

Liposome mediated dissipation of valinomycin-imposed potassium potential across erythrocytes membrane.

Influence of liposomes made of phosphatidylcholine (PC) on the valinomycin-imposed potassium potential across erythrocyte membrane was examined by measuring the fluorescence change of the potential-sensitive cyanine dye. We concluded that the liposomes modulate ion selectivity of the membrane embedded valinomycin, on the basis of the following lines of evidence. (i) The valinomycin-imposed potassium potential across erythrocyte membrane (interior negative) was dissipated in the presence of PC-liposomes. (ii) When PC-liposomes were added to the cell suspension before the valinomycin, a membrane potential could not be imposed. (iii) Liposomes containing only the PC of saturated fatty acids were inactive in the potential dissipation, whereas the liposomes containing PC of unsaturated fatty acids were fully active. (iv) Liposome-mediated dissipation of the imposed-membrane potential was similarly observed in the resealed erythrocyte ghosts. (v) The liposomes did not show a detectable effect on the gramicidin-mediated proton potential. (vi) The effect of liposome was somewhat analogous to the nigericin-mediated dissipation of the valinomycin-imposed potassium potential.

Animals↗

PubMed1986

Reduced toxicity and enhanced antitumor effects in mice of the ionophoric drug valinomycin when incorporated in liposomes.

Valinomycin (NSC 122023) is a cyclic depsipeptide antibiotic with potassium selective ionophoric activity. This drug has been reported to display antitumor effects but its utilization has been limited by its extreme toxicity. Here we report that the incorporation of valinomycin into multilamellar liposomes composed of dimyristoyl phosphatidyl choline:cholesterol:phosphatidyl serine (10:4:1 M ratio) results in a profound reduction in toxicity with maintainence of antitumor efficacy. Thus the median lethal dose (LD50) for i.p. administered valinomycin (VM) in C57BL/6 X DBA/2 mice is 1.7 mg/kg whereas the LD50 for liposome incorporated valinomycin (MVL-VM) is in excess of 50 mg/kg. In like manner, the LD50 for i.v. administered VM is 0.18 mg/kg where the LD50 for MLV-VM preparations passed through a 0.6-micron filter is greater than 10 mg/kg. The antitumor efficacies of i.p. administered VM or MLV-VM against i.p. P388 mouse leukemia were similar in multiple dose formats using doses below the maximal tolerated dose for VM. However, since MLV-VM was substantially less toxic than VM, the liposomal drug also produced significant (170% median survival time of treated mice/median survival time of untreated control) antitumor effects when administered as a single dose at levels above the maximal tolerated dose for free VM; single doses of free VM at the maximal tolerated dose were ineffective in this context. In experiments with i.v. inoculated P388 leukemia, MLV-VM but not free VM, displayed antitumor activity (144% median survival time of treated mice/median survival time of untreated control) when administered i.v. at equitoxic doses. Thus the use of a lipid vesicle drug carrier system permits a reduction in the toxicity of valinomycin with maintainence or enhancement of antitumor activity against i.p. or i.v. P388 leukemia.

Animals↗

PubMed1996

Modification of cation selectivity of valinomycin by complexing it with an anion: delta pH decay studies.

The relaxation times associated with the delta pH decay by the combined action of valinomycin and substituted phenols have been measured with potassium ions (tau K) and sodium ions (tau Na) in soyabean phospholipid vesicle suspensions (delta pH = pH difference across vesicular membrane). In these experiments the compensating charge flux of alkali metal ions limits the rate of delta pH decay. The large deviation of the ratio tau Na/tau K from the concentration ratio [valinomycin-K+]/[valinomycin-Na+] reflects the change in the cation selectivity of valinomycin on complexing with phenolates. The observed reduction in the cation selectivity can be understood by noting that the binding sites of Na+ and K+ on valinomycin are different and that the anion binds at a site closer to that of Na+. Our data also suggest that the steric factors associated with the anions affect the magnitude of electrostatic interaction responsible for the increased stability of the sodium complex.

Cations, Monovalent↗

PubMed1967

The effect of valinomycin on the ionic permeability of thin lipid membranes.

Optically black membranes prepared from sheep red cell lipids have a high electrical resistance (1-3 x 10(8) ohm-cm(2)). The ionic transference numbers (T(i)) for cations (Na(+) or K(+)) are equal to each other but at least four to five times greater than for Cl(-). The cyclic depsipeptide valinomycin produces a striking decrease in the membrane resistance when K(+), but not when Na(+) is in the solutions bathing the membrane. The ratio T(Na)/T(K), estimated from membrane voltages in the presence of ionic concentration gradients, approaches zero. The order of membrane monovalent cation selectivity, in the presence of valinomycin, is H(+) > Rb(+) > K(+) > Cs(+) > Na(+). Addition of the antibiotic to one side of a membrane which separates identical solutions of NaCl produces a substantial (up to 80 mV) membrane voltage (side opposite valinomycin negative). These data are consistent with the hypothesis that valinomycin can interact with appropriately sized cations (hydrated diameter ??? 6 A) to increase their membrane permeability, perhaps by forming hydrogen bonds between the solvation shell of the cations and carbonyl oxygens in the valinomycin molecule which are directed toward the aperture of the ring.

Animals↗

PubMed2006

Valinomycin-proton interaction in low-polarity media.

Valinomycin is shown to form a stable complex with protons in the form of H3O+ ions. Using 1H and 13C nuclear magnetic resonance (NMR), Fourier transform (FT) infrared spectroscopy, and ab initio-density functional theory (DFT) quantum mechanical calculations, it is shown that H3O+, produced by hydrogen bis(1,2-dicarbollyl) cobaltate (HDCC) in the presence of water, interacts with valinomycin in 1,1,2,2-tetrachloroethane-d2 to give a relatively stable complex. The equilibrium constant K of the complex formation was derived from chemical shifts in 1H-NMR, its value being 5.9. The proton affinity constant estimated from this value taking into account HDCC dissociation is 10(5.3), i.e., high enough to be relevant under physiological conditions. Under suitable conditions there is a fast exchange of H3O+ between valinomycin molecules, the exchange correlation time being of the order of 10(-4) s. The instantaneous structure of the complex is slightly asymmetric, the H3O+ ion being strongly hydrogen-bonded to three of the six ester carbonyl groups and weekly bound to the residual ones by electrostatic interactions. This asymmetry is averaged by fast reorientation and displacement of H3O+ so that the molecule appears to be symmetric in the time window of NMR. The results indicate that valinomycin could serve as a carrier for proton transfer across a biological membrane.

Algorithms↗

PubMed1996

Reversal of multidrug resistance by valinomycin is overcome by CCCP.

Reversal of P-glycoprotein-mediated multidrug resistance by valinomycin is overcome by the proton ionophore, CCCP. This effect, a complete suppression of the 5- to 10-fold valinomycin-induced reversal ("re-reversal"), exhibits a sharp extracellular potassium concentration ([K+(0)]) dependence. It is observed at [K+(0)] > 2-4 mM and not at [K+(0)] greater than or equal to 2 mM, in the case of the fluorescent substrates rhodamine 123 and daunorubicin. The fact that "re-reversal" is detected only for the combination of CCCP with valinomycin raises the possibility that a direct interaction between these ionophores may explain the phenomenon. We show spectroscopic evidence of such an interaction, with a [K+(0)]-dependence similar to that of the "re-reversal." These data suggest that the reversal of P-glycoprotein activity by valinomycin can be compromised by anionic compounds such as CCCP due to complex formation. More generally, molecular interactions involving P-glycoprotein substrates or reversing agents may significantly affect drug accumulation in multidrug resistant cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1993

Alternative pathways of apoptosis induced by methylprednisolone and valinomycin analyzed by flow cytometry.

Apoptosis of murine thymocytes induced by either methylprednisolone or valinomycin was studied by flow cytometry. The apoptosis induced by methylprednisolone followed three stages: an initial decrease in cell volume, indicated by a fall in forward scatter accompanied by faint ethidium bromide staining, a second stage in which the cells became brightly stained by ethidium bromide, and a final stage when the cells were apparently less fluorescent as the nuclei disintegrated into apoptotic bodies. As the forward scatter of cells decreased there was a simultaneous depolarization of the cells and an elevation of intracellular calcium. These early changes preceded the fragmentation of the DNA which also preceded the intense staining of the cells by ethidium bromide. Methylprednisolone-induced apoptosis was inhibited by low concentrations (1 x 10(-7) M) of valinomycin and nonactin, neither of which could themselves induce apoptosis at these low concentrations. Cadmidazolium and cycloheximide arrested the program at an early stage. Okadaic acid allowed volume loss and ethidium bromide staining to proceed in the absence of DNA fragmentation. At high concentrations (1 x 10(-5) M) valinomycin induced a form of apoptosis, but nonactin only caused the cells to fragment. The valinomycin-induced apoptosis, although it involved the degradation of DNA and the disintegration of the nuclei into apoptotic bodies, differed from the methylprednisolone apoptosis as it did not involve a decrease of cell volume and was not inhibited by cycloheximide or affected by okadaic acid.

Animals↗

PubMed1976

Optical and electrical studies on dansyllysine-valinomycin in thin lipid membranes.

Dansyllysine-valinomycin, a fluorescent analogue of the ionophore valinomycin was synthesized and incorporated into black lipid membranes. Its concentration inside the membrane was measured fluorometrically and was also determined from electrical relaxation experiments, which were analyzed on the basis of a previously proposed carrier model. The results of both methods agreed within less than one order of magnitude. This appears satisfactory in view of the sources of error inherent in both procedures. A conductance increment per carrier molecule of about 3 - 10(-17) omega-1 was obtained for dansyllysine-valinomycin in diphytanoyllecithin membranes at 25 degrees C and 1 M RbCl in the aqueous phases. This is about 400 times smaller compared to unmodified valinomycin in monoolein membranes. The difference is mainly caused by the change in the membrane properties and to a smaller extent by the structural modification of the carrier.

Electric Conductivity↗

PubMed1976

Pigment containing lipid vesicles. II. Interaction of valinomycin with lecithin as sensed by chlorophyll a.

Valinomycin added to a suspension of chlorophyll a containing lecithin vesicles induces slight changes in the spectrum of chlorophyll a. These changes are measured as a difference spectrum between samples with and without valinomycin but of otherwise identical composition. The analysis of the experiments reveals that the effect is neither associated with the ionophoric properties of valinomycin nor due to a direct interaction of this agent with chlorophyll a. The molar ratio of valinomycin dissolved in the membrane to lecithin is found to be the relevant parameter, thus indicating an interaction between these two components. As a consequence, the aggregational state of the lecithin molecules is altered. Chlorophyll a incorporated into the membrane acts as a sensor, i.e. it reflects the alteration by a change in its spectroscopic parameters.

Chlorophyll↗

PubMed1978

Neurite formation and membrane changes of mouse neurobalstoma cells induced by valinomycin.

A clonal cell line of mouse neuroblastoma cells was found to undergo morphological differentiation in the presence of a K+ ionophore, valinomycin, in the assay medium. This effect was blocked by increasing the concentration of KCl of the medium, suggesting that the changes in resting membrane potential and ion fluxes may be involved in the mechanism of the formation of neurites. No enhancement of the neurite formation was observed in salines containing high concentrations of KCl in the absence of valinomycin. Depolarizing agents including veratridine, gramicidin and ouabain did not stimulate the outgrowth of neurites. Neither electrophoretic mobility of the cells nor molecular anisotropy of fluorescence probes in the membranes was modified by the treatment of valinomycin. Instead, it modified the slow binding phase in kinetics of the interaction of 1-anilinonaphthalene-8-sulfonate (ANS) with the cells, which is related to the penetration process of the probe into membranes. Valinomycin also enhanced the fluorescence intensity of ANS by increasing the binding sites in neuroblastoma cells.

Anilino Naphthalenesulfonates↗