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PubMed1979

Effect of cholesterol on the valinomycin-mediated uptake of rubidium into erythrocytes and phospholipid vesicles.

Human erythrocytes have been treated with lipid vesicles in order to alter the cholesterol content of the cell membrane. Erythrocytes have been produced with cholesterol concentrations between 33 and 66 mol% of total lipid. The rate of valinomycin-mediated uptake of rubidium into the red cells at 37 degrees C was lowered by increasing the cholesterol concentration of the cell membrane. Cholesterol increased the permeability to valinomycin at 20 degrees C of small (less than 50 nm), unilamellar egg phosphatidylcholine vesicles formed by sonication. Cholesterol decreased the permeability to valinomycin at 20 degrees C of large (up to 200 nm) unilamellar egg phosphatidylcholine vesicles formed by freeze-thaw plus brief sonication. It is concluded that cholesterol increases the permeability of small membrane vesicles to hydrophobic penetrating substances while above the transition temperature but has the opposite effect on large membrane vesicles and on the membranes of even larger cells.

Adult↗
PubMed1982

Effects of valinomycin on lymphocytes independent of potassium permeability.

10(-7) M valinomycin affects human lymphocytes in the following manner: (1) it is non-toxic; (2) it inhibits mitogenesis; (3) it causes a reduction in cell ATP; and (4) it causes a marked increase in steady-state Na+ exchange. However, it has a minimal effect on cell ion (K+, Na+, Ca2+, Mg2+) contents and no effect whatever on K+ exchange. Neither the fast nor the slow fraction of steady-state K+ exchange is affected by 10(-7) M valinomycin. The various reported effects of valinomycin on lymphocyte functions cannot be assumed to be due to changes in plasma membrane K+ permeability. The mechanism of the increase in steady-state Na+ exchange, and whether or not it is related to inhibition of mitogenesis, are unsettled issues.

Adenosine Triphosphate↗
PubMed1989

Comparison of effects of a potassium channel opener BRL34915, a specific potassium ionophore valinomycin and calcium channel blockers on endothelin-induced vascular contraction.

The effects of a potassium (K+) channel opener BRL34915 and a specific K+ ionophore valinomycin on vasoconstriction induced by endothelin (ET) were compared with those of calcium (Ca2+) channel blockers, nicardipine and verapamil, using helical strips from rat thoracic aorta. ET induced potent and persistent contraction in control solution and similar but smaller contraction in Ca2+-free solution. BRL34915 and valinomycin inhibited the ET-induced contraction dose-dependently in control solution, but not in Ca2+-free solution. The ET-induced contraction was also inhibited by nicardipine and verapamil, though less strongly. On the other hand, high K+ (35 mM)-induced vasoconstriction was strongly inhibited by nicardipine and verapamil, but not by BRL34915 or valinomycin. These results support the idea that the extracellular Ca2+-dependent component of the ET-induced contraction may be mediated by Ca2+ influx by a route other than voltage-dependent Ca2+-channels.

Animals↗
PubMed1988

Effect of calcium and temperature on mixed lipid-valinomycin monolayers. A comparison of glycosphingolipids (ganglioside GT1b, sulphatides) and phosphatidylcholine.

The influence of calcium and temperature on pure lipid (bovine brain PC, sulphatides, ganglioside GT1b), valinomycin and mixed lipid-valinomycin monolayers at the air/water interface was studied. In mixed films, evidence was found that the two components were miscible. On the other hand, at higher surface pressures, phase separation occurs in the cases of PC and sulphatides. Measuring the area requirement and the collapse pressure the stability of both lipid and the peptide was increased in particular due to ganglioside-valinomycin interaction. The addition of 10(-5) M calcium into the subphase at 20 and 37 degrees C and surface pressures of 10 and 20 mN/m led to a condensing effect in ganglioside mixtures, with formation of aggregates as indicated also by the nearly ideal behaviour of two component monolayers.

Calcium↗
PubMed2005

The effect of the presence of valinomycin on the interfacial tension of lecithin membrane.

The effect of the presence of valinomycin in lecithin membrane on its interfacial tension has been studied. The experiments have been carried out at various forming solution compositions and at various potassium ion concentrations in electrolyte solution. Potassium chloride was used as the electrolyte. A complex was formed between the valinomycin molecule and K+ ion. The following parameters describing the complex were determined: K, the stability constant of the valinomycin-K+ complex and B, partition coefficient. These values are equal to 3.52 x 10(5) m3 mol(-1) and 6.0, respectively.

Anti-Bacterial Agents↗
PubMed2006

Valinomycin-induced apoptosis in Chinese hamster ovary cells.

Accumulating evidence endorses that excessive K(+) efflux is an ionic mechanism underlying apoptosis both in neuronal and non-neuronal cells. K(+) channels play important roles in mediating the pro-apoptotic K(+) efflux. Chinese hamster ovary (CHO) cells have been widely used for gene transfection experiments. These cells lack detectable endogenous voltage-gated K(+) channels. We were interested in knowing whether the absence of endogenous K(+) channels would render wild-type CHO cells more resistant to apoptotic death. We also wished to determine if direct stimulation of K(+) efflux would trigger apoptosis in these cells. Exposing CHO cells to hypoxia (1% O(2)) or to a typical apoptotic insult of serum deprivation for up to 24h did not affect cell survival. On the other hand, the K(+) ionophore valinomycin caused substantial cell death within 12h of its application. Valinomycin-treated CHO cells underwent several apoptotic events, including phosphatidylserine (PS) membrane translocation, caspase-3 activation, and mitochondrial membrane depolarization during the first few hours of exposure. Reducing K(+) efflux by elevating extracellular K(+) concentrations noticeably attenuated valinomycin-induced cell death. This study reinforces a K(+) efflux-mediated apoptotic mechanism in CHO cells and may help to explain the unique feature of their higher tolerance to apoptosis.

Animals↗
PubMed1997

Role of metal ion free valinomycin-carbonyl cyanide m-chlorophenylhydrazone complex in the enhancement of the rates of gramicidin facilitated net H+, Li+ and Na+ transport across phospholipid vesicular membrane.

The studies on the decay of the pH difference, delta pH, across soyabean phospholipid vesicular membrane have shown that the rates of net proton transport and the associated Li+ and Na+ ion transport across the membrane can be enhanced by the combined action of gramicidin, valinomycin and carbonyl cyanide m-chlorophenylhydrazone (CCCP) in K(+)-free vesicle solutions. The data obtained under different experimental conditions suggest that this enhancement is a consequence of facilitation of CCCP- transport (1) by complexing CCCP- with the highly membrane permeant valinomycin without the metal ion bound to it and (2) by the associated Li+ or Na+ transport through the gramicidin channel such that no net charge is transported across the membrane. The dissociation constant of the weak valinomycin-CCCP- complex has been estimated to be > 200 mM in the membrane. The delta pH in these experiments were created by temperature jump.

Carbonyl Cyanide m-Chlorophenyl Hydrazone↗
PubMed1981

Structure of valinomycin-K+ complex in solution by extended x-ray absorption fine structure.

We used synchrotron radiation to measure the K-edge absorption spectra of the potassium ion in valinomycin-K+ complexes dissolved in ethanol and methanol. Our motivation is to study the structure of valinomycin around the potassium ion and the effect of solvents. From the extended x-ray absorption fine structure, we found that the mean distance from potassium to its coordination atoms, oxygen, is the same for both solvents, 2.79 +/- 0.02 A, compared with 2.76 A in crystal. The K-edge threshold spectra of the two solutions are almost identical but have a small difference in their relative peak intensities. The coincidence of their corresponding peak positions indicates that the strength of ligand field is about the same in these two samples. This agrees with the known binding energies of potassium ion to valinomycin in solutions. The difference in the relative peak intensities suggests a perturbation of ligand symmetry by solvents.

Chemical Phenomena↗
PubMed1995

The mechanism of ion conduction by valinomycin: analysis of charge pulse responses.

Even though valinomycin has been employed and studied extensively for over 30 years, the attempts to explain its mechanism have not been entirely successful. The basic carrier model uses four rate constants that describe association of an ion and carrier, transfer of the complex across the membrane, dissociation of the complex, and transfer of the free carrier back across the membrane. If the basic model is correct all of these constants are independent of ion concentration. In previous work with rubidium the rate constants for transfer of free carrier, transfer of complexes, and dissociation were independent of the concentration, but the rate constant for association varied markedly. No satisfactory explanation for these observations was proposed. In this study current relaxations after charge pulses have been analyzed using digital data acquisition, a Bayesian algorithm, and inspection of linear plots of residuals. In agreement with previous results the relaxations for sufficiently high rubidium or potassium concentrations contain three exponential components, but the rate constants for association and dissociation decrease to similar extents as ion concentration increases. A simple extension of the carrier model to allow a more realistic description of association and dissociation is in good agreement with the rate constants fitted in the present study but not those for low ion concentrations found in previous work. At high ion concentrations the rate-limiting step in association appears to be a change in the conformation of the free carrier preceding the bimolecular association reaction. Transfer of neutral, free valinomycin between the surfaces is slower than the transfer of the charged ion-valinomycin complexes. Transfer of the complex may be hastened by deformation of the membrane, or transfer of the free carrier may be slowed by a need for conformation changes.

Algorithms↗
PubMed1978

Structure analysis of small proteins by electron microscopy: valinomycin, bacitracin and low molecular weight cell growth stimulators.

Dark field electron microscopy was combined with optical filtering to study at high resolution the structure of the cyclopeptide antibiotics, bacitracin and valinomycin, and two proteins of unknown structure, LMW-CSA N and B, low molecular weight granulocyte colony stimulating activity isolated from medium conditioned with normal or leukemic leukocytes. For bacitracin and valinomycin the images faithfully represented the known structural features at a resolution of 0.5 nm or better, depicting a two-ring structure for bacitracin, as well as the position of the potassium ion in valinomycin. Both proteins of unknown structrue had at least one cyclic peptide portion. LMW-CSA N had a size of 2.0 nm, LMW-CSA B of 2.4 nm. A potential site of the calcium ionophoric activity in the latter protein was found to be in the larger of the two ring portions constituting the molecule.

Bacitracin↗
PubMed1985

High-resolution solid-state 13C NMR study of free and metal-complexed macrocyclic antibiotic ionophores valinomycin, nonactin, and tetranactin: conformational elucidation in solid and solution by conformation-dependent 13C chemical shifts.

We recorded high-resolution 13C NMR spectra of the macrocyclic antibiotic ionophores valinomycin, nonactin, and tetranactin in the solid state by the cross-polarization-magic angle spinning (CP-MAS) method, in order to gain insight into the use of conformation-dependent 13C chemical shifts as a convenient means to delineate a conformational change induced by metal ion complexation. The 13C peak splittings in the solid state are consistent with the symmetry properties of the ionophores as revealed by X-ray diffraction: C2 symmetry in free tetranactin and S4 or S6 symmetry for a variety of metal complexes of nonactin and tetranactin or the K+ complex of valinomycin, respectively. Interestingly, many of the 13C NMR peaks of carbons in the skeletal backbones were significantly displaced (up to 8 ppm). The displacements of the peaks were explained by a conformational change as characterized by variations of torsion angles. Accordingly, we were able to obtain conformational features of Na+ and Cs+ complexes of valinomycin, for which X-ray diffraction data are unavailable, on the basis of the displacements of the 13C NMR peaks. Further, we discuss conformational features of these complexes in chloroform solution, with reference to those observed in the solid state.

Anti-Bacterial Agents↗
PubMed1988

NMR study of the interactions of polymyxin B, gramicidin S, and valinomycin with dimyristoyllecithin bilayers.

The interactions of three polypeptide antibiotics (polymyxin B, gramicidin S, and valinomycin) with artificial lecithin membranes were studied by nuclear magnetic resonance (NMR). Combination of 31P and 2H NMR allowed observation of perturbations of the bilayer membrane structure induced by each of the antibiotics in the regions of the polar headgroups and acyl side chains of the phospholipids. The comparative study of the effects of these membrane-active antibiotics and the lipid bilayer structure demonstrated distinct types of antibiotic-membrane interactions in each case. Thus, the results showed the absence of interaction of polymyxin B with the dimyristoyllecithin membranes. In contrast, gramicidin S exhibited strong interaction with the lipid above the gel to liquid-crystalline phase transition temperature: disordering of the acyl side chains was evident. Increasing the concentration of gramicidin S led to disintegration of the bilayer membrane structure. At a molar ratio of 1:16 of gramicidin S to lecithin, the results are consistent with coexistence of gel and liquid-crystalline phases of the phospholipids near the phase transition temperature. Valinomycin decreased the phase transition temperature of the lipids and increased the order parameters of the lipid side chains. Such behavior is consistent with penetration of the valinomycin molecule into the interior of the lipid bilayers.

Dimyristoylphosphatidylcholine↗
PubMed1979

Conformations of an ion-binding cyclic peptide analogue of valinomycin, cyclo(L-Val-Gly-Gly-L-Pro)3.

A 270-MHz 1H nuclear magnetic resonance investigation of an ion-binding cyclic peptide analogue of valinomycin, cyclo(L-Val-Gly-Gly-L-Pro)3, and its cation complexes is reported. In CD2Cl2 and CDCl3, the peptide is proposed to occur in a C3-symmetric conformer with the N--H's of all six glycine residues intramolecularly hydrogen bonded. This conformation is different from the familiar valinomycin bracelet structure and lacks any "cavity". Cations do not bind, or bind only weakly, to the peptide in these solvents. Uncomplexed cyclo(L-Val-Gly-Gly-L-Pro)3 in acetonitrile appears to be averaging among several conformations with no evidence found for any preferred intramolecular hydrogen bonds. The strong 1:1 complexes of cyclo(L-Val-Gly-Gly-L-Pro)3 with K+ ANd Ba2+ in acetonitrile are structurally analogous to the bracelet conformation of valinomycin and involve the N--H's of the Val residues and of the Gly's preceding Pro in intramolecular hydrogen bonding. Tl+ was also found to form strong 1:1 complexes with the dodecapeptide.

Glycine↗
PubMed1983

Measurement of the intramitochondrial volume in hepatocytes without cell disruption and its elevation by hormones and valinomycin.

Methods have been developed to measure the lysophospholipid content and matrix volume of liver cell mitochondria in situ in order to test the hypothesis that these parameters may be important in the hormonal control of mitochondrial function [Armston, Halestrap & Scott (1982) Biochim. Biophys. Acta 681, 429-439]. No change in the labelling of mitochondrial lysophospholipids with [32P]Pi was detected after treatment of liver cells with glucagon, phenylephrine or vasopressin. Incorporation of [32P]Pi into mitochondrial phosphatidylinositol was enhanced by phenylephrine and vasopressin. Mitochondrial volumes were measured using rapid disruption of cells by sonication into 3H2O and [14C]sucrose or without cell disruption using 3H2O and [14C]mannitol. In control cells the two methods gave values of 1.09 and 0.40 microliters/mg of mitochondrial protein respectively, which represent 19 and 7% respectively of the total cell volume measured with 3H2O and inulin [14C]carboxylic acid. Both methods showed that glucagon, phenylephrine and 1 nm-valinomycin produced significant increases (13% and 26% using sucrose and mannitol respectively) in mitochondrial volume. The increase was coincident with the stimulation of gluconeogenesis from L-lactate and pyruvate and of mitochondrial respiratory chain activity. The effects of glucagon and phenylephrine were additive on both mitochondrial volume and respiratory chain activity, but not on gluconeogenesis. Liver cells exposed to gluconeogenic hormones or low concentrations of valinomycin showed a decrease in light scattering at 520 nM correlating with the change in mitochondrial volume but without a change in whole-cell volume. The time course and hormone sensitivity of this response were similar to those for the hormonal stimulation of gluconeogenesis. The light-scattering response to glucagon, phenylephrine and vasopressin, but not to valinomycin, were greatly reduced or abolished in Ca2+-free media.

Animals↗
PubMed1994

Voltage dependence of DIDS-insensitive chloride conductance in human red blood cells treated with valinomycin or gramicidin.

Net K and Cl effluxes induced by valinomycin or by gramicidin have been determined directly at varied external K, denoted by [K]o, in the presence and absence of the anion transport inhibitors DIDS (4,4'-diiso-thiocyano-2,2'-disulfonic acid stilbene), and its less potent analogue SITS (4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid). The results confirm that pretreatment with 10 microM DIDS, or 100 microM SITS, for 30 min at 23 degrees C inhibits conductive Cl efflux, measured in the continued presence of the inhibitors at 1 mM [K]o, by only 59-67%. This partial inhibition by 10 microM DIDS at 1 mM [K]o remains constant when the concentration of DIDS, or when the temperature or pH during pretreatment with DIDS, are increased. Observations of such partial inhibition previously prompted the postulation of two Cl conductance pathways in human red blood cells: a DIDS-sensitive pathway mediated by capnophorin (band 3 protein), and a DIDS-insensitive pathway. The present experiments demonstrate that at [K]o corresponding to values of EK between -35 and 0 mV the DIDS-insensitive component of net Cl efflux is negligible, being < or = 0.1 muMol/g Hb/min, both with valinomycin (1 microM) and with gramicidin (0.06 microgram/ml). At lower [K]o, where EK is below approximately -35 mV, the DIDS-insensitive fraction of net Cl efflux increases to 2.6 muMol/g Hb/min with valinomycin (1 microM), and to 4.8 muMol/g Hb/min with gramicidin (0.06 microgram/ml). With net fluxes determined from changes in mean cell volume, and with membrane potentials measured from changes in the external pH of unbuffered red cell suspensions, a current-voltage curve for DIDS-insensitive Cl conductance has been deduced. While specific effects of varied [K]o on net Cl efflux are unlikely but cannot strictly be ruled out, the results are consistent with the hypothesis that DIDS-insensitive Cl conductance turns on at an Em of approximately -40 mV.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1997

Electrodiffusion, barrier, and gating analysis of DIDS-insensitive chloride conductance in human red blood cells treated with valinomycin or gramicidin.

Current-voltage curves for DIDS-insensitive Cl- conductance have been determined in human red blood cells from five donors. Currents were estimated from the rate of cell shrinkage using flow cytometry and differential laser light scattering. Membrane potentials were estimated from the extracellular pH of unbuffered suspensions using the proton ionophore FCCP. The width of the Gaussian distribution of cell volumes remained invariant during cell shrinkage, indicating a homogeneous C1- conductance among the cells. After pretreatment for 30 min with DIDS, net effluxes of K+ and Cl- were induced by valinomycin and were measured in the continued presence of DIDS; inhibition was maximal at approximately 65% above 1 microM DIDS at both 25 degrees C and 37 degrees C. The nonlinear current-voltage curves for DIDS-insensitive net Cl- effluxes, induced by valinomycin or gramicidin at varied [K+] o, were compared with predictions based on (1) the theory of electrodiffusion, (2) a single barrier model, (3) single occupancy, multiple barrier models, and (4) a voltage-gated mechanism. Electrodiffusion precisely describes the relationship between the measured transmembrane voltage and [K+]o. Under our experimental conditions (pH 7.5, 23 degrees C, 1-3 microM valinomycin or 60 ng/ml gramicidin, 1.2% hematocrit), the constant field permeability ratio PK/PCl is 74 +/- 9 with 10 microM DIDS, corresponding to 73% inhibition of PCl. Fitting the constant field current-voltage equation to the measured Cl- currents yields PCl = 0.13 h-1 with DIDS, compared to 0.49 h-1 without DIDS, in good agreement with most previous studies. The inward rectifying DIDS-insensitive Cl- current, however, is inconsistent with electrodiffusion and with certain single-occupancy multiple barrier models. The data are well described either by a single barrier located near the center of the transmembrane electric field, or, alternatively, by a voltage-gated channel mechanism according to which the maximal conductance is 0.055 +/- 0.005 S/g Hb, half the channels are open at -27 +/- 2 mV, and the equivalent gating charge is -1.2 +/- 0.3.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1971

The effect of valinomycin on the electrical properties of solutions of red cell lipids in n-decane.

This paper reports the electrical properties of thick lipid membranes in the absence and presence of valinomycin. The thick lipid membranes were formed by placing a solution of sheep red cell lipids in decane between two cellophane partitions which formed the interfaces between the membrane and the two aqueous bathing solutions. The DC electrical resistance of these structures was found to be directly proportional to the reciprocal of the concentration of lipids in the decane (C(L)). The limiting resistance, as (C(L) (-1)) approached zero, was 3 x 10(8) ohm-cm(2). Resistance was also found to be linearly related to membrane thickness. The limiting resistance at zero thickness was again 1-3 x 10(8) ohm-cm(2). These data are interpreted to indicate that the DC resistance of thick lipid membranes comprises two surface resistances (R(S)) at each interface with the aqueous bathing solutions, and a bulk resistance (R(B)) of the lipid-decane solution, arranged in series. Measurements of the effect of variations of area on resistance were consistent with this interpretation. Valinomycin reduced R(S) but had no effect on R(B). Under certain conditions, thick lipid membranes containing valinomycin behaved like highly selective K(+) electrodes.

Animals↗
PubMed1981

Ion transport mediated by the valinomycin analogue cyclo(L-Lac-L-Val-D-Pro-D-Val)3 in lipid bilayer membranes.

Cyclo(L-Lac-L-Val-D-Pro-D-Val)3 (PV-Lac) a structural analogue of the ion-carrier valinomycin, increases the cation permeability of lipid bilayer membranes by forming a 1:1 ion-carrier complex. The selectively sequence for PV-Lac is identical to that of valinomycin; i.e., Rb+ greater than K+ greater than Cs+ greater than or equal to NH+4 greater than Na+ greater than Li+. The steady-state zero-voltage conductance, G(0), is a saturating function of KCl concentration. A similar behavior was found for Rb+, Cs+, and NH+4. However, the ion concentration at which G(0) reaches a plateau strongly depends on membrane composition. The current-voltage curves present saturating characteristics, except at low ion concentrations of Rb+, K+, or Cs+. The ion concentration at which the saturating characteristics appear depends on membrane composition. These and other results presented in this paper agree with a model that assumes complexation between carrier and ion at the membrane-water interface. Current relaxation after voltage-jump studies were also performed for PV-Lac. Both the time constant and the amplitude of the current after a voltage jump strongly depend on ion concentration and membrane composition. These results, together with the stationary conductance data, were used to evaluate the rate constants of the PV-Lac-mediated K+ transport. In glycerolmonooleate they are: association rate constant, 2 x 10(6) M-1 s-1; dissociation rate constant, 4 x 10(5) s-1; translocation rate constant for complex, 5 x 10(4) s-1; and the rate of translocation of the free carrier (ks), 55 s-1. ks is much smaller for PV-Lac than for valinomycin and thus limits the efficiency with which the carrier is able to translocate cations across the membrane.

Biological Transport↗