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PubMed1992

Valinomycin and excitation-contraction coupling in skeletal muscle fibres of the frog.

1. Experiments were carried out on intact frog skeletal muscle fibres to study the role of H+ and K+ as counter-ions during the release of Ca2+ from the sarcoplasmic reticulum (SR). A specific focus was to test whether valinomycin, a potassium ionophore, markedly reduces or abolishes H+ counter-ions fluxes across the SR membrane in response to electrical stimulation. 2. Single twitch fibres, mounted on an optical bench apparatus and stretch to long sarcomere length (3.6-4.0 microns), were activated by single action potentials (16 degrees C). Two optical signals related to excitation-contraction coupling were measured: (i) the 'second component' of the intrinsic birefringence signal, which is closely related to the myoplasmic free [Ca2+] transient, and (ii) the transient myoplasmic alkalization (delta pH) detectable from the pH indicator Phenol Red, a signal thought to reflect the movement of protons from the myoplasm into the SR in partial electrical exchange for released Ca2+. 3. Exposure of a fibre to 5 microM-valinomycin produced a slight, progressive decrease in the amplitude of the birefringence signal, approximately 5-6% per hour. This result suggests that, if anything, the peak rate at which Ca2+ is released from the sarcoplasmic reticulum is slightly decreased by valinomycin. 4. The amplitude of the Phenol Red delta pH signal, measured after exposure of a fibre to valinomycin for a period of at least 60 min, averaged 0.0020 +/- 0.0002 (+/- S.E.M.); this value is slightly smaller than, but not significantly different from (P greater than 0.05; two-tailed t test) that measured in fibres not exposed to valinomycin (0.0025 +/- 0.0002). This result does not support the idea that valinomycin, but virtue of increasing the flux of K+ into the SR, markedly reduces the flux of protons during Ca2+ release. 5. Our findings of minimal changes in the birefringence and delta pH signals are consistent with the idea that, at the time of Ca2+ release, the potassium conductance of the SR membrane is large and not substantially increased by the addition of valinomycin to Ringer solution.

Action Potentials↗
PubMed1985

Selective effects by valinomycin on cytotoxicity and cell cycle arrest of transformed versus nontransformed rodent fibroblasts in vitro.

The effect of submicromolar concentrations of the K+ ionophore valinomycin on proliferation, viability, distribution of cell population over phases of the cell cycle, and cellular adenosine triphosphate content of different permanent rodent cell lines in vitro was investigated. Valinomycin inhibits proliferation of all cell lines tested with a saturating effect at about 20 to 100 nM. The effect of valinomycin on nontransformed 3T3 mouse and Rat-1 cells is nontoxic, whereas it acts with increasing toxicity on the transformed cells in the order 3T6 mouse, polyoma-3T3 mouse, temperature-sensitively Rous sarcoma virus-transformed Rat-1 at permissive temperature, and SV40-3T3 cells. According to these and some other criteria, the essential action of valinomycin appears to be to impose on the cells at low growth densities a state of limiting growth condition which normally is encountered only at high cell densities and/or low serum concentration. Nontransformed cells are proliferation arrested by valinomycin essentially in the G1 phase of the cell cycle, whereas all transformed cells under this condition are not arrested selectively in G1. In all cell lines tested (3T3, 3T6, and SV40-3T3), cellular adenosine triphosphate content is decreased by about 33% upon treatment with 20 nM valinomycin. Evidence is presented for a mitochondrial site of action of valinomycin.

Adenosine Triphosphate↗
PubMed1993

Direct and indirect effects of valinomycin upon cytochrome c oxidase.

Valinomycin binds beef heart cytochrome c oxidase with approximately equimolar stoichiometry (one valinomycin per cytochrome aa3 complex) and a Kd of 2.0-3.0 microM, almost independent of ionic strength, but dependent upon the presence of K+ ions. Its effects are twofold: a red shift in the Soret maximum of the resting enzyme from 419 to 422 nm, with an appreciable delta EmM at 430-410 nm, and an inhibition of catalytic activity of about 50%. Much smaller concentrations of valinomycin are sufficient to induce the release of respiration in cytochrome oxidase vesicles by nigericin. Intermediate levels of valinomycin alone are capable of partially releasing respiratory control, probably by increasing H+ permeability as well as that of K+. The amounts of valinomycin required to bind the enzyme are much greater than those required to collapse delta psi in vesicular systems in a steady state or during proton pulse experiments. We conclude that the two effects--a direct one upon the enzyme and an indirect one via abolition of electrogenic potentials--are of separate origins. The existence of the direct effect does not call for reinterpretation of classical results showing proton translocation, which are adequately explained by the indirect action of valinomycin as an ionophore.

Animals↗
PubMed1979

Kinetics of ion transport in lipid membranes induced by lysine-valinomycin and derivatives.

Lysine-valinomycine and two N epsilon-acyl derivatives are compared with respect to their potency to transport Rb+ ions across thin lipid membranes. Lysine-valinomycin acts as a neutral ion carrier only above a pH of about 7 of the aqueous solutions, while at lower pH the molecules seem to be positively charged due to a protonation of the epsilon-NH2 group of the lysine residue. A kinetic analysis based on voltage jump relaxation experiments and on the nonlinearity of the current-voltage characteristics showed that the conductance increment delta per carrier molecule for uncharged lysine-valinomycin is similar to that of natural valinomycin. The attachment of a rather bulky side group such as the dansyl or para-nitrobenzyloxycarbonyl group reduced delta by approximately one order of magnitude. Some of the relaxation data of the valinomycin analogues were influenced by an unspecific relaxation of the pure lipid membrane. This structural relaxation represents a limitation to the possibility of analyzing specific transport systems in thin lipid membranes by the voltage jump or charge pulse techniques. It is shown that the time dependence of this structural relaxation--which was first published by Sargent (1975)--is at variance with a three capacitor equivalent circuit of the membrane, which was suggested by Coster and Smith (1974) on the basis of a.c. measurements. A modified equivalent circuit has been found to represent a satisfactory analogue for the current relaxation in the presence of valinomycin. It turned out, however, that such an equivalent circuit provides little insight into the molecular mechanism of transport.

Biological Transport↗
PubMed1975

Increase of potassium flux by valinomycin in embryonic chick heart.

The effect of different concentrations of the antibiotic valinomycin, was determined on 42K efflux and Na, K content of embryonic chick hearts. Valinomycin produces an increase of K efflux which is progressive in time and markedly dependent on the concentration of external K (0-5 mM) and valinomycin (10(-8) to 10(-5) M). The changes in K efflux is not due to a reversal of the Na-K pump mechanism, secondary to ATP depletion: i) the increase of K efflux by valinomycin persists in the absence of external Na ions. ii) analysis of Na and K content and 42K influx measurements with and without valinomycin indicate that active K influx is not inhibited in a solution containing 0.5 mM K and only slightly decreased in a solution containing 5 mM K. Valinomycin, acting as a K carrier, presumably increases K conductance of the cell membrane resulting in a rise in K efflux.

Animals↗
PubMed1979

The effect of surface charge density on valinomycin-K+ complex formation in model membranes.

The model membrane approach was used to investigate the surface charge effect on the ion-antibiotic complexation process. Mixed monolayers of valinomycin and lipids were spread on subphases containing K+ or Na+. The surface charge density was modified by spreading ionizable valinomycin analogs on aqueous subphases of different pH or by changing the nature of the lipid (neutral, negatively charged) in the mixed film. Surface pressure and surface potential measurements demonstrated that a neutral lipid (phosphatidylcholine) or positively charged valinomycin analogs didn't enhance the anti-biotic complexing capacity. However, a maximal complexation is reached for a critical lipid concentration in the valinomycin-phosphatidylserine mixed film. The role of the surface charge on the valinomycin complexing properties was examined in terms of the Gouy-Chapman theory. As a consequence of the negative charge of the lipid monolayer, the K+ concentration near the surface is larger than the bulk concentration, by a Boltzmann factor. A good agreement was observed between the experimental results and the theoretical predictions. Conductance measurements of asymmetric bilayers containing a neutral lipid (egg lecithin) on one side and a negatively charged lipid (phosphatidyl-serine) on the other, confirm the role of the surface charge. Indeed, addition of K+ to the neutral side of the bilayer containing valinomycin had no effect on the conductance whereas addition of K+ to the charged side of the bilayer caused a 80-fold conductance increase.

Kinetics↗
PubMed1993

Monolayer characteristics of valinomycin in the presence of various salts in aqueous subphase.

The surface pressure-molecular area, surface potential-molecular area and Brewster reflectivity-molecular area isotherms for valinomycin monolayers (states II and III) at various aqueous salt subphases were measured. Two additional states of valinomycin monolayers were observed in the presence of K+ and Rb+ as compared to the other alkali metal cations. This phenomenon correlates with the strong complexation between the valinomycin and these cations in bulk. State II corresponds to the very special 'bangle' conformation of the polypeptide ring of valinomycin, in which all carbonyl and carboxyl groups of the amino-acid residues are coordinated to the cation inside the polypeptide ring. State III corresponds to the vertical orientation of the 'bangle' conformation of valinomycin molecules with respect to the interface. An influence of the anion size on the stability of valinomycin-cation complexes at the interface was found.

Potassium Chloride↗
PubMed1984

Effect of valinomycin on membrane vesicle aggregation of porcine intestinal brush borders.

It has been found in the brush border membrane vesicles from porcine small intestine that valinomycin causes vesicle aggregation and that Ca2+-induced aggregation of the vesicles is saturably stimulated in the presence of valinomycin. The apparent half-maximal concentration of valinomycin required to enhance the Ca2+ effect on the membrane aggregation is approximately 40 microM. Results of a fluorometric study using 1-anilino-8-naphthalene sulfonate (ANS) showed that the addition of valinomycin to the membranes induces slight decreases in the ANS-binding affinities for the membranes in the presence and absence of Ca2+. On the other hand, measurements of the incorporation rate of 1,6-diphenyl-1,3,5-hexatriene (DPH) into the vesicles and of anisotropies of DPH-labeled membranes suggested that the lipid organization of the membranes was not altered upon the addition of valinomycin. From these results, it was suggested that the valinomycin effect on the membrane aggregation is mainly related to the nature of the membrane surface charge.

Anilino Naphthalenesulfonates↗
PubMed2000

Inhibition of human NK cell function by valinomycin, a toxin from Streptomyces griseus in indoor air.

Streptomyces griseus strains isolated from indoor dust have been shown to synthesize valinomycin. In this report, we show that human peripheral blood lymphocytes treated with small doses (30 ng ml(-1)) of pure valinomycin or high-pressure liquid chromatography-pure valinomycin from S. griseus quickly show mitochondrial swelling and reduced NK cell activity. Larger doses (>100 ng/ml(-1)) induced NK cell apoptosis within 2 days. Within 2 h, the toxin at 100 ng ml(-1) dramatically inhibited interleukin-15 (IL-15)- and IL-18-induced granulocyte-macrophage colony-stimulating factor and gamma interferon (IFN-gamma) production by NK cells. However, IFN-gamma production induced by a combination of IL-15 and IL-18 was somewhat less sensitive to valinomycin, suggesting a protective effect of the cytokine combination against valinomycin. Thus, valinomycin in very small doses may profoundly alter the immune response by reducing NK cell cytotoxicity and cytokine production.

Air Microbiology↗
PubMed1997

Valinomycin induces apoptosis of ascites hepatoma cells (AH-130) in relation to mitochondrial membrane potential.

Valinomycin is a potassium ionophore, and is well known to cause the collapse of the mitochondrial membrane potential. It has been reported that loss of mitochondrial membrane potential is observed in the early stages of apoptosis induced by various agents. Thus, the effects of valinomycin on tumor cells were examined. Valinomycin induced uncoupling of respiration and depolarization of isolated mitochondria. Depolarization of intact mitochondria in AH-130 rat ascites hepatoma cells was also induced by valinomycin. Valinomycin induced apoptosis revealing the typical apoptotic characteristics such as fragmentation and ladder formation of DNA, shrinkage of cells, and formation of pycnotic nucleus. There was a correlation between the depolarization of mitochondria and DNA fragmentation. After depolarization of mitochondria, the activity of caspase-3-like protease but not caspase-1-like protease increased markedly. In contrast, this apoptosis did not involve the release of reactive oxygen species from mitochondria, increase in intracellular calcium concentration, or protein synthesis. In addition, anti-apoptotic members of the Bcl-2 family (Bcl-xL and Bcl-2) were not correlated with apoptosis. These results indicate that valinomycin might induce apoptosis through degradation of the mitochondrial membrane potential. Taken together, these observations suggest that there may be a mechanism that transmits the signal from mitochondrial depolarization to subsequent apoptosis execution steps.

Animals↗
PubMed1991

The influence of valinomycin induced membrane potential on erythrocyte shape.

In addition to previous observations indicating that membrane potential changes generated by various Donnan- and Nernst-potentials lead to erythrocyte shape transformations, we show in this paper that diffusion potential change, induced by valinomycin, governs erythrocyte shape transformations. In low KCl-medium valinomycin, transferring the positive Nernst-potential into a negative diffusion potential, transforms stomatocytes into echinocytes. Using modified erythrocytes with a reversed K/Na ratio, even positive diffusion potentials can be induced by valinomycin. In these cases, stomatocytes can be generated by valinomycin. It is shown that, additionally, valinomycin in large concentrations is itself stomatocytogenic, and that the fluorescent dye diS-C3-(5) also induces stomatocytes. This, however, is a side effect which does not contradict the potential dependence of shape transformation. Using non washed erythrocytes, resuspended in plasma, valinomycin, inducing negative diffusion potential, transforms most erythrocytes to echinocytes despite the stomatocytogenic effect of albumin.

Albumins↗
PubMed2004

A study of the conformations of valinomycin in solution phase.

Vibrational absorption and vibrational circular dichroism (VCD) spectra of valinomycin are measured, in different solvents, in the ester and amide carbonyl stretching regions. The influence of cations, namely Li(+), Na(+), K(+), and Cs(+), in methanol-d(4) solvent is also investigated. Ab initio quantum mechanical calculations using density functional theory and 6-31G* basis set are used to predict the absorption and VCD spectra. A bracelet-type structure for valinomycin that reproduces the experimental absorption and VCD spectra in inert solvents is identified. For the structure of valinomycin in polar solvents, a propeller-type structure was optimized, but further investigations are required to confirm this structure. A symmetric octahedral environment for the ester carbonyl groups in the valinomycin-K(+) complex is supported by the experimental VCD spectra. The results obtained in the present study demonstrate that even for large macrocyclic peptides, such as valinomycin, VCD can be used as an independent structural tool for the study of conformations in solution.

Amino Acid Sequence↗
PubMed2006

NMR evidence of a valinomycin-proton complex.

In addition to the well-known complexes of valinomycin with alkali metal cations, an equimolar complex of the same compound with proton was found to be formed in nitrobenzene. Hydrogen bis(1,2-dicarbollylide) cobaltate (HDCC) was used as a proton source. According to NMR spectra, the complex formation is quantitative at proton/valinomycin molar ratios up to 1:1 but there is fast exchange of protons between coordinated and uncoordinated valinomycin molecules at lower ratios. 1H and 13C NMR spectra show a dramatic change in the valinomycin conformation during its coordination with protons, probably from a propeller-like to a bracelet-like form. As valinomycin is one of the well-known ion-carrying ionophores facilitating especially the K+ ion transport across a biological membrane, the existence of the valinomycin-proton complex could be important in biochemistry and biology.

Magnetic Resonance Spectroscopy↗
PubMed1980

Interaction between membrane properties and protein synthesis in reticulocytes: influence of trypsinization on [3H]-valinomycin action.

Using [3H]-Valinomycin we show here that two types of sites can be described for this cyclic depsipeptide. A first type is sensitive to low concentration of trypsin while the other, more internal, is uncovered by the use of the protease. Of these two kinds of sites, the more external one seems more concerned with the effect that Valinomycin has on protein synthesis in rabbit reticulocytes. However, when a high concentration of Valinomycin is used, all the sites can be occupied even those which can be revealed only by tripsinization. In this case, even prolonged trypsin action does not result in release of the protein synthesis inhibitory action of Valinomycin. It is concluded that hydrophobic sites are occupied by Valinomycin only after the cell surface has been saturated by hydrophylic bonds with the antibiotic.

Animals↗
PubMed1978

Transport of organic anions through the erythrocyte membrane as K+-valinomycin complexes.

K+, Rb+, or Cs+ complexes of valinomycin form ion pair complexes with picric acid and trinitrobenzenesulfonate (TNBS). The formation of a picrate-K+-valinomycin complex is supported by spectral evidence. These complexes have zero net charge and readily permeate the intact erythrocyte membrane. The K+-valinomycin complex has been used to convert the nonpenetrating TNBS into a penetrating covalent probe, making it as useful vectorial probe to measure accessible amino groups of proteins and phospholipids on both sites of the erythrocyte membrane. The enhanced transport of TNBS into the cell by valinomycin is dependent on external K+ in the medium. The entry of TNBS into the cell is manifested by an increased labeling of hemoglobin and membrane phosphatidylethanolamine (PE). Stilbeneisothiocyanatedisulfonate (SITS) and anilinonaphthalenesulfonate (ANS) inhibit both the basal and K+-valinomycin stimulated labeling of PE and hemoglobin by TNBS. The data suggest two independent effects of ANS and SITS, one mediated by an inhibition of the anion transport protein and another by the incorporation of these hydrobic anions into the cell membrane with an increase in negative charge on the membrane which leads to an inhibition of TNBS permeation into the cell by electrostatic repulsion.

Anilino Naphthalenesulfonates↗
PubMed1986

Flux ratio of valinomycin-mediated K+ fluxes across the human red cell membrane in the presence of the protonophore CCCP.

The ratio of valinomycin-mediated unidirectional K+ fluxes across the human red cell membrane, has been determined in the presence of the protonophore carbonylcyanide m-chlorophenylhydrazone, CCCP, using the K+ net efflux and 42K influx. The driving force for the net efflux (Vm - EK+) has been calculated from the membrane potential, estimated by the CCCP-mediated proton distribution and the Nernst potential for potassium ions across the membrane. An apparent driving potential for the K+ net efflux has been calculated from the K+ flux ratio, determined in experiments where the valinomycin and CCCP concentrations were varied systematically. This apparent driving force, in conjunction with the actual driving force calculated on basis of the CCCP estimated membrane potential, is used to calculate a flux ratio exponent, which represents an estimate of the deviation of valinomycin-mediated K+ transport from unrestricted electrodiffusion, when protonophore is present. In the present work, the flux ratio exponent is found to be 0.90 when the CCCP concentration is 5.0 microM and above, while the exponent decreases to about 0.50 when no CCCP is present. The influence of CCCP upon the rate constants in the valinomycin transport cycle is discussed. The significance of this result is that red cell membrane potentials are overestimated, when calculated from valinomycin-mediated potassium isotope fluxes, using a constant field equation.

Carbonyl Cyanide m-Chlorophenyl Hydrazone↗
PubMed1986

Potassium transport in the rabbit renal proximal tubule: effects of barium, ouabain, valinomycin, and other ionophores.

Potassium fluxes in a suspension of rabbit proximal tubules were monitored using a potassium-sensitive extracellular electrode. Ouabain (10(-4) M) and barium (5 mM) were used to selectively quantitate the potassium efflux pathway (105 +/- 5 nmol K+ X mg protein-1 X min-1) and the sodium pump-related potassium influx (108 +/- 7), respectively. These equal and opposite fluxes suggest that potassium accumulation in the cell occurs mainly through the sodium pump and that potassium efflux occurs mainly through barium-sensitive potassium channels. Thus the activity of the sodium pump (Na,K-ATPase) in the basolateral membrane of the proximal tubule is balanced by the efflux of potassium, presumably across the basolateral membrane, which has a high potassium permeability. In addition, the effect of valinomycin and other ionophores was examined on potassium fluxes and several metabolic parameters [oxygen consumption (QO2), ATP content]. The addition of valinomycin to the tubules produced a net efflux of potassium which was quantitatively equivalent to the efflux produced by the addition of ouabain. The valinomycin-induced efflux was mainly due to the activity of valinomycin as a mitochondrial uncoupler, which indirectly inhibited the sodium pump by allowing a rapid reduction of the intracellular ATP. Amphotericin, nystatin, and monensin all produced large net releases of intracellular potassium. The action of the ionophores could be localized to the plasma or mitochondrial membrane and classified into three groups, as follows: those which demonstrated full mitochondrial uncoupler activity (FCCP, valinomycin), those which had no uncoupler activity (amphotericin B, nystatin); and those which displayed partial uncoupler activity (monensin, nigericin).

Animals↗
PubMed1994

Phosphate, nitrendipine and valinomycin increase the Ca2+/ATP coupling ratio of rat skeletal muscle sarcoplasmic reticulum Ca(2+)-ATPase.

Nitrendipine and valinomycin act synergistically to stimulate ATP-dependent Ca2+ accumulation by rat skeletal muscle sarcoplasmic reticulum vesicles 3-fold. The stimulation is not caused by activation of the Ca(2+)-ATPase or by inhibition of the sarcoplasmic reticulum Ca2+ channel, but is due to an increased efficiency of transport by Ca(2+)-loaded vesicles. At low Ca2+ concentrations, nitrendipine+valinomycin inhibits Ca2+ uptake by increasing the Ca2+ KM but does not effect equilibrium Ca2+ binding to the Ca(2+)-ATPase (Kd = 0.75 microM). In the presence of 50 mM phosphate, nitrendipine+valinomycin increases the steady-state coupling ratio (Ca2+ accumulated per ATP hydrolyzed) from 0.6 to 1.9 by decreasing the rate of ATP hydrolysis by 72%, while reducing the Ca2+ accumulation rate by only 13%. The rates of both passive and Ca(2+)-ATPase-mediated Ca2+ release are reduced by nitrendipine+valinomycin. The data indicate that nitrendipine and valinomycin act directly on the Ca(2+)-ATPase to decrease the ATP hydrolysis rate, increase the Ca2+ KM, decrease Ca2+ efflux, and increase the Ca2+/ATP coupling ratio of Ca(2+)-loaded vesicles.

Adenosine Triphosphate↗