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At least 667 records · Page 37Linked to original sources
PubMed1997

Mitochondrial involvement in post-tetanic potentiation of synaptic transmission.

Posttetanic potentiation (PTP) is an essential aspect of synaptic transmission that arises from a persistent presynaptic [Ca2+]i following tetanic stimulation. At crayfish neuromuscular junctions, several inhibitors of mitochondrial Ca2+ uptake and release (tetraphenylphosphonium or TPP+, carbonyl cyanide m-chlorophenylhydrazone or CCCP, and ruthenium red) blocked PTP and the persistence of presynaptic residual [Ca2+]i, while endoplasmic reticulum (ER) Ca2+ pump inhibitors and release channel activators (thapsigargin, 2,5-di-(tert-butyl)-1,4-benzohydroquinone or BHQ, and caffeine) had no effects. PTP apparently results from the slow efflux of tetanically accumulated mitochondrial Ca2+.

Animals↗
PubMed1998

In vivo prevention of cyclophosphamide-induced Ca2+ dependent damage of rat heart and liver mitochondria by cyclosporin A.

The use of Cyclophosphamide, an anti-cancer and immunosuppressant drug, is accompanied by a number of side effects. Rats injected with a single dose of cyclophosphamide (200 mg kg-1 body weight) showed an increase in the levels of serum glutamate-oxaloacetate transaminase, serum glutamate-pyruvate transaminase, glucose-6-phosphate dehydrogenase and creatine phosphokinase isoenzyme by 53, 24, 55 and 135%, respectively. Also the ability of heart or liver mitochondria to retain accumulated Ca2+ and tetraphenylphosphonium ion was sharply affected in treated rats. Rats injected with the same dose of cyclophosphamide plus cyclosporin A (500 micrograms kg-1 body weight) showed reduction in the levels of those enzymes by about 44, 21, 43 and 57%, respectively compared to cyclophosphamide-treated rats. Cyclosporin A treatment also restored mitochondrial ability to retain accumulated Ca2+ and tetraphenyl phosphonium ions nearly to the level of untreated rats. We suggest that cyclophosphamide induced cardio and hepatotoxicity by increasing heart and liver inner mitochondrial membrane permeability to Ca2+. The protective effect of cyclosporin A against cyclophosphamide-induced damage also support this suggestion.

Alanine Transaminase↗
PubMed1997

Membrane potential manipulation in synaptic plasma membrane vesicles for studying neurotransmitter uptake and release.

Synaptic plasma membrane (SPM) vesicles represent a membrane fraction very useful in studying non-vesicular neurotransmitter release. The procedure described here to isolate SPM vesicles from a crude synaptosomal fraction of sheep brain cortex is quick, simple (ultracentrifugation in a discontinuous density gradient of dextran T110), and combines a high yield (130 micrograms/g brain) with a satisfactory grade of purification. The preparation of SPM vesicles consists of vesicles (approximately 0.54 +/- 0.8 micron diameter) delimited by a single membrane with the native orientation. We are able to ascertain these characteristics on the basis of morphology studies (electron microscopy observations), enzyme activities (Na+/K(+)-ATPase, Ca2+/Mg(2+)-ATPase, acetylcholinesterase and glucose-6-phosphatase), biochemical composition (lipid and protein analysis) and the tetrodotoxin sensitivity of the veratridine-induced gamma-aminobutyric acid (GABA) release. Isolating the SPM vesicles by the proposed procedure permits manipulating the ionic gradients across the membrane by changing the ion concentrations on either side or by utilizing specific ionophores. The vesicles retain their various activities, including their capacity for neurotransmitter uptake and release assays for at least 3 months, when preserved at -70 degrees C. Furthermore, the vesicles permit depicting the electrochemical gradients across the membranes into chemical and electrical components. We describe the use of the tetraphenylphosphonium cation (TPP+) to dissipate the membrane potential (delta psi) of the vesicles, while preserving ionic gradients. The characteristics of the lipid-soluble cation TPP+ allows a massive inflow of this cation into vesicular compartments and a consequent depolarization.

Animals↗
PubMed2001

Spectral characteristics of 2-aminodiphenylamine in different solvents and at various pH values.

The absorption and fluorescence spectra of 2-aminodiphenylamine (2ADA) have been studied as a function of solvent polarity and acid concentration. Analysis of solvatochromic and prototropic shifts of 2ADA reveals: (i) the presence of intramolecular hydrogen bonding between imino and amino groups in the ground state, (ii) dual fluorescence (360 and 430 nm) of the monocation (2ADA+) formed by the protonation of amino group; and (iii) proton-induced quenching of the monocation (2ADA+) fluorescence. In the dual fluorescence of 2ADA+, the longer wavelength emission at 430 nm is found to be from the twisted form of the monocation. The rate constants of the proton-induced quenching of 2ADA+ are determined.

Hydrogen-Ion Concentration↗
PubMed2002

Full dimensional calculations of vibrational energies of H3O+ and D3O+.

We report full dimensional calculations of vibrational energies of H3O+ and D3O+ using two implementations of the code MULTIMODE. In one implementation, the reference geometry is the minimum of the potential (the standard choice for MULTIMODE). This implementation is not able to readily describe splittings in the vibrational energies due to motion through the inversion barrier. A second implementation, in which the reference geometry is the inversion saddle point, is able to describe the splittings. These full dimensional calculations are done using the realistic, though not spectroscopically accurate, potential of Ojamae, Singer and Shavitt, and the results are compared with experiment.

Chemical Phenomena↗
PubMed2005

Generation of cycloalkynes by hydro-iodonio-elimination of vinyl iodonium salts.

Cyclohexynes can be generated efficiently from 1-cyclohexenyliodonium salts with acetate or other bases via the E2 and E1 mechanism. The observed regioselectivity of nucleophilic addition to substituted cyclohexynes conforms to the LUMO populations: the less deformed acetylenic carbon is more electrophilic. Cycloheptyne can form by the E1-type elimination via 1,2-rearrangement from cyclohexylidenemethyliodonium salt under very weakly basic conditions.

Acetylene↗
PubMed1992

Lipophilic cations: a group of model substrates for the multidrug-resistance transporter.

The possibility that simple lipophilic cations such as tetraphenylphosphonium (TPA+), triphenylmethylphosphonium (TPMP+), and diphenyldimethylphosphonium (DDP+) are substrates for the multidrug-resistance transport protein, P-glycoprotein, was tested. Hamster cells transfected with and overexpressing mouse mdr1 or mouse mdr3 exhibit high levels of resistance to TPP+ and TPA+ (20-fold) and somewhat lower levels of resistance to TPMP+ and DDP+ (3-12-fold). Transfected cell clones expressing mdr1 or mdr3 mutants with decreased activity against drugs of the MDR spectrum (e.g., Vinca alkaloids and anthracyclines) also show reduced resistance to lipophilic cations. Studies with radiolabeled TPP+ and TPA+ demonstrate that increased resistance to cytotoxic concentrations of these lipophilic cations is correlated quantitatively with a decrease in intracellular accumulation in mdr1- and mdr3-transfected cells. This decreased intracellular accumulation is shown to be strictly dependent on intact intracellular nucleotide triphosphate pools and is reversed by verapamil, a known competitive inhibitor of P-glycoprotein. Taken together, these results demonstrate that lipophilic cations are a new class of substrates for P-glycoprotein and can be used to study its mechanism of action in homologous and heterologous systems.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Activation energy for permeation of phosphonium cations through phospholipid bilayer membrane.

The conductance caused by translocation of various phosphonium cations across phospholipid (from soybean) bilayer membrane was measured. Phosphonium cations used were tetraphenylphosphonium (TPP+) and triphenylalkylphosphonium cations formulated as (Phe)3-P(+)-(CH2)nCH3 (n = 0-5). The conductance was dependent on voltage applied externally to the membrane in accordance with a theory developed by previous authors. Using the theory, values of beta K(i) were determined, where beta and k(i) are a linear partition coefficient and a rate constant of transmembrane ion transport, respectively. Since beta k(i) depended on the phosphonium ion concentration, values extrapolated to infinite dilution, (beta k(i))0, were determined. Temperature dependence of (beta k(i))0 allowed us to estimate the activation energy of transport, Ea. For TPP+ thermodynamic values obtained were consistent with values calculated by Flewelling and Hubbell [(1986) Biophys. J. 49, 541-552]. When (Phe)3-P(+)-(CH2)nCH3 (n = 0-5) were used, E(a) depended on the odd or even of n. This "odd and even" pattern was observed in a variety of phenomena such as solubility in water, equivalent ionic conductivity in water, and 31P NMR chemical shift.

Biological Transport↗
PubMed1994

Characterization of saxitoxin binding to saxiphilin, a relative of the transferrin family that displays pH-dependent ligand binding.

Saxiphilin is a 91 kDa saxitoxin-binding protein that is homologous to members of the transferrin family of Fe(3+)-binding proteins noted for pH-dependent release of Fe3+. The mechanism of toxin binding to purified native saxiphilin from the bullfrog (Rana catesbeiana) was studied using [3H]saxitoxin. At pH 7.4 and 0 degrees C [3H]saxitoxin binds to a single site on saxiphilin with a KD of approximately 0.2 nM. The pH dependence of [3H]saxitoxin binding follows a one-site titration curve in the range of pH 9-4 with maximal binding from pH 9 to 7 and half-inhibition at pH 5.7. Inhibition of toxin binding at low pH is the combined result of a decrease in the rate of toxin association and an increase in the rate of toxin dissociation. The dependence of the apparent rate constants for [3H]saxitoxin association and dissociation on [H+] can be accounted for by a four-state model of allosteric interaction between the toxin-binding site and a single titratable residue of saxiphilin with a pKa of 7.2 in the toxin-free form and 4.3 in the toxin-bound form. From 0 to 25 degrees C, the temperature dependence of [3H]saxitoxin binding to saxiphilin is characterized by delta H degrees = -8.3 kcal mol-1, delta S degrees = 13.8 cal mol-1 K-1, and activation energies of 22.5 kcal mol-1 for dissociation and 11.1 kcal mol-1 for association. Binding of [3H]saxitoxin to saxiphilin is competitively inhibited with low affinity by a variety of divalent metal and lanthanide cations. Inhibition of toxin binding by the carboxyl-methylating reagent trimethyloxonium is prevented by pre-equilibration with [3H]saxitoxin, implicating the presence of one or more carboxyl groups in the binding site. Functional similarities suggest that the saxitoxin-binding site of saxiphilin is located in an interdomain cleft analogous to the location of one of the two homologous Fe(3+)-binding sites of transferrins. On the basis of residue substitutions between saxiphilin and transferrins, it is proposed that the saxitoxin-binding site is located in the carboxy terminal lobe of saxiphilin and that binding is modulated by protonation of a conserved histidine residue.

Amino Acid Sequence↗
PubMed1982

A method for rapid, continuous monitoring of solute uptake and binding.

A method has been developed for dynamically monitoring the free concentration of diffusible, tritiated solutes. The technique utilizes particles of a solid scintillator microencapsulated in gel beads that are permeable to diffusible label. Since tritium beta radioactivity has an effective range in water of only a few micrometers, only label that is free to diffuse through the gel can excite the scintillator, while sequestered label is effectively excluded. Thus, the scintillation light output monitors the freely diffusible concentration of label exclusively. A simple, preliminary encapsulation technique is described and tested, and the theory behind the method is discussed with regard to the time resolution attainable for a given label concentration and type of encapsulation. The feasibility of the method is demonstrated by measuring the uptake of [3H]tetraphenylphosphonium by Escherichia coli membrane vesicles in response to the generation of a membrane potential (interior negative).

Glucose↗
PubMed1983

Covalent labeling of the acetylcholine receptor from Torpedo electric tissue with the channel blocker [3H]triphenylmethylphosphonium by ultraviolet irradiation.

The lipophilic cation [3H]triphenylmethylphosphonium, frequently used as a voltage sensor in membrane systems, binds reversibly to a site different from the acetylcholine binding site. This is concluded from the different pH dependences of the binding of these two ligands. Furthermore [3H]triphenylmethylphosphonium, previously identified as a channel blocker, can be covalently incorporated into acetylcholine receptor-rich membranes from Torpedo electric tissue by UV irradiation of the receptor-ligand complex. In the absence of effector, predominantly the alpha-polypeptide chains (Mr 40000) of the receptor protein are labeled by the radioactive ligand. The agonist carbamoylcholine strongly stimulates the labeling, but it directs the label predominantly to the delta- and beta-polypeptide chains. The antagonist D-tubocurarine and the virtually irreversible competitive antagonist alpha-bungarotoxin have qualitatively the same effect as the agonist carbamoylcholine. Significant differences were obtained with receptor-rich membranes prepared from Torpedo marmorata and Torpedo californica: No agonist- or antagonist-stimulated reaction was observed with the latter. The results are interpreted as an indication of a rearrangement of the receptor's quaternary structure caused by cholinergic effector binding preceding discrimination between agonists and antagonists.

Acetylcholine↗
PubMed1984

Rapid laser flash photoaffinity labeling of binding sites for a noncompetitive inhibitor of the acetylcholine receptor.

Photoaffinity labeling of the nicotinic acetylcholine receptor from Torpedo marmorata electric tissue was performed in the presence of cholinergic effectors in the millisecond to second time range by a combination of a stopped-flow apparatus and a high-energy pulse laser. The label applied was [3H]triphenylmethylphosphonium, a lipophilic cation previously shown to be a specific blocker of the acetylcholine receptor ion channel. With the receptor in the resting state most of the label was incorporated into the alpha polypeptide chains. In the presence of agonists and antagonists increasing incorporation into the delta- and (less pronounced) the beta-chain was observed. The time course of this increase had a half-life of about 0.4 s, being slower than receptor activation and channel opening. in the resting, active, and even rapidly desensitized state, the alpha polypeptide chains appear to be the primary targets of the photoaffinity reaction. The action spectrum of the photolabeling has a sharp maximum at lambda = 270 nm and a small-side maximum at lambda = 290 nm. It does not resemble the absorption spectrum of the label and may hint at amino acid side chains as the moieties activated by UV light causing the photolabeling. The effector specificity of the observed slow increase of label incorporation into the delta polypeptide chain was investigated. It does not prove that slow desensitization is the underlying event. The agonists acetylcholine and carbamoylcholine as well as treatment of receptor-rich membranes with phospholipase A2 (but not phospholipase D) triggered labeling of delta, but antagonists such as D-tubocurarine and most conspicuously flaxedil had a similar effect.

Affinity Labels↗
PubMed1987

Modification of myosin subfragment 1 tryptophans by dimethyl(2-hydroxy-5-nitrobenzyl)sulfonium bromide.

Modification of tryptophanyl residues (Trps) of myosin subfragments 1 (S-1) was performed with dimethyl(2-hydroxy-5-nitrobenzyl)sulfonium bromide (DHNBS). Under controlled conditions, pH 6 at 0 degrees C and 10-min reaction with 10-100-fold molar excess, K+(EDTA) activity was reduced down to less than half, whereas Ca2+-ATPase activity increased and acto-S-1-ATPase was not affected. The number of modified Trps (up to 2.5) agreed well with the number of 2-hydroxy-5-nitrobenzyl moieties incorporated in S-1. The thiol groups of S-1 were not affected up to 50-fold molar excess of DHNBS, thus indicating that the modification was selective for Trps. The modification of as few as one Trp caused a blue shift of the emission spectrum, accompanied by a reduction in the fluorescence quantum yield. The accessibility of Trps to the fluorescence quencher acrylamide is drastically reduced upon modification, indicating that DHNBS-reactive Trps are more "exposed" than the DHNBS-refractive ones. DHNBS modification did not seem to affect the ATP-induced tryptophan fluorescence enhancement of S-1. The effect of DHNBS modification of the intrinsic fluorescence of S-1 indicates that the modified Trps are located in a polar environment and that they may be identical with the long-lifetime Trps of Torgerson [Torgerson, P. (1984) Biochemistry 23, 3002-3007]. The most reactive Trp is located in the N-terminal 27-kDa fragment of the S-1 heavy chain. It might also be inferred from the above data that the nonexposed and ATP-perturbed Trp(s) is (are) located in the 50-kDa fragment.

Actins↗
PubMed1989

Functional modification of a Ca2+-activated K+ channel by trimethyloxonium.

Single Ca2+-activated K+ channels from rat skeletal muscle plasma membranes were studied in neutral phospholipid bilayers. Channels were chemically modified by briefly exposing the external side to the carboxyl group modifying reagent trimethyloxonium (TMO). TMO modification, in a "multi-hit" fashion, reduces the single-channel conductance without affecting ion selectivity. Modification also shifts the voltage activation curve toward more depolarized voltages and reduces the affinity of the channel blocker charybdotoxin (CTX). CTX, bound to the channel during the TMO exposure, prevents the TMO-induced reduction of the single-channel conductance. These data suggest that the high-conductance Ca2+-activated K+ channel has carboxyl groups on its external surface. These groups influence ion conduction, gating, and the binding of CTX.

Animals↗
PubMed1980

Electrochemical proton gradient across the cell membrane of Halobacterium halobium: effect of N,N'-dicyclohexylcarbodiimide, relation to intracellular adenosine triphosphate, adenosine diphosphate, and phosphate concentration, and influence of the potassium gradient.

The proton motive force across the cell membrane of halobacterial cells has been estimated and compared to intracellular values of ATP, ADP, and inorganic phosphate concentrations with respect to the chemiosmotic hypothesis. The accumulation of 14C-labeled indicator substances, triphenylmethylphosphonium for the membrane potential and 5,5-dimethyloxazolidine-2,4-dione for the pH difference between the cell interior and the medium, has been measured in the cells. Values up to 270 mV for the proton motive force have been found in cells pretreated with N,N'-dicyclohexylcarbodiimide (DCCD, 10(-4) M, 30 degrees C, 12 h). Upon illumination a high membrane potential is generated, which is then gradually replaced by a large pH difference. Cells treated with lower DCCD concentrations show only an enhancement of membrane potential upon illumination; the pH difference remains at a low level. Under anaerobic dark conditions, untreated cells maintain a proton motive force of 120-140 mV, which is equilibrated with the intracellular levels of ATP, ADP, and inorganic phosphate. The pH gradient is 1 unit at pH 6 but 0 at pH 8. The membrane potential is low (60-80 mV) at pH 6 and high (120-130 mV) at pH 8. We propose that the proton translocating ATPase compensates for the lowered pH difference at high external pH values by enhancing the membrane potential. The concentration difference of the potassium ions influences the proton motive force and the intracellular ATP levels, apparently via its action on the membrane potential. When the difference of the chemical potential of the potassium ion, expressed in millivolts, exceeds the preexisting membrane potential, the intracellular ATP level is enhanced. When the difference of the chemical potential of the potassium ion (millivolts) is smaller than the membrane potential, the ATP level is decreased.

Adenosine Diphosphate↗
PubMed1980

Electrochemical proton gradient across the cell membrane of Halobacterium halobium: comparison of the light-induced increase with the increase of intracellular adenosine triphosphate under steady-state illumination.

The increase of the proton motive force mediated by bacteriorhodopsin is compared to the intracellular ATP concentration under steady-state illumination. The membrane potential was measured via the accumulation of the lipophilic ion [14C]triphenylmethylphosphonium and the pH gradient via the accumulation of the weak acid 5,5-dimethyloxazolidine-2,4-dione. Light causes a parallel increase of ATP level and membrane potential at an external pH of 8. In contrast, at pH 6 an increase of the intracellular ATP concentration occurs without a corresponding increase of the proton motive force. If the extracellular NaCl concentration is reduced and not replaced by other ions, no membrane potential at all can be measured at pH 6-7; nonetheless, light-induced ATP synthesis occurs. A significant enhancement of the pH gradient occurs only at irradiances higher than those required for the attainment of the maximal intracellular ATP concentration. In the presence of the uncoupler carbonyl cyanide m-chlorophenylhydrazone it is possible to obtain light-induced ATP synthesis without a measurable proton motive force in basal salt at pH 8. It is concluded that if bacteriorhodopsin acts as a proton pump, then the pumped protons can be used for ATP synthesis before they equilibrate with the protons in the extracellular bulk phase.

Adenosine Diphosphate↗