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PubMed2001

Re-engineering monovalent cation binding sites of methylamine dehydrogenase: effects on spectral properties and gated electron transfer.

Methylamine dehydrogenase (MADH) is a tryptophan tryptophylquinone (TTQ)-dependent enzyme that catalyzes the oxidative deamination of primary amines. Monovalent cations are known to affect the spectral properties of MADH and to influence the rate of the gated electron transfer (ET) reaction from substrate-reduced MADH to amicyanin. Two putative monovalent cation binding sites in MADH have been identified by X-ray crystallography [Labesse, G., Ferrari, D., Chen, Z.-W., Rossi, G.-L., Kuusk, V., McIntire, W. S., and Mathews, F. S. (1998) J. Biol. Chem. 273, 25703-25712]. One requires cation-pi interactions involving residue alpha Phe55. An alpha F55A mutation differentially affects these two monovalent cation-dependent phenomena. The apparent K(d) associated with spectral perturbations increases 10-fold. The apparent K(d) associated with enhancement of the gated ET reaction becomes too small to measure, indicating that either it has decreased more than 1000-fold or the mutation has caused a conformational change that eliminates the requirement for the cation for the gated ET. These results show that of the two binding sites revealed in the structure, cation binding to the distal site, which is stabilized by the cation-pi interactions, is responsible for the spectral perturbations. Cation binding to the proximal site, which is stabilized by several oxygen ligands, is responsible for the enhancement of the rate of gated ET. Another site-directed mutant, alpha F55E MADH, exhibited cation binding properties that were the same as those of the native enzyme, indicating that interactions with the carboxylate of Glu can effectively replace the cation-pi interactions with Phe in stabilizing monovalent cation binding to the distal site.

Bacterial Proteins↗
PubMed2006

Reactions of methyl fluoride with atomic transition-metal and main-group cations: gas-phase room-temperature kinetics and periodicities in reactivity.

Reactions of CH(3)F have been surveyed systematically at room temperature with 46 different atomic cations using an inductively coupled plasma/selected-ion flow tube tandem mass spectrometer. Rate coefficients and product distributions were measured for the reactions of fourth-period atomic ions from K(+) to Se(+), of fifth-period atomic ions from Rb(+) to Te(+) (excluding Tc(+)), and of sixth-period atomic ions from Cs(+) to Bi(+). Primary reaction channels were observed corresponding to F atom transfer, CH(3)F addition, HF elimination, and H(2) elimination. The early-transition-metal cations exhibit a much more active chemistry than the late-transition-metal cations, and there are periodic features in the chemical activity and reaction efficiency that maximize with Ti(+), As(+), Y(+), Hf(+), and Pt(+). F atom transfer appears to be thermodynamically controlled, although a periodic variation in efficiency is observed within the early-transition-metal cations which maximizes with Ti(+), Y(+), and Hf(+). Addition of CH(3)F was observed exclusively (>99%) with the late-fourth-period cations from Mn(+) to Ga(+), the fifth-period cations from Ru(+) to Te(+), and the sixth-period cations from Hg(+) to Bi(+) as well as Re(+). Periodic trends are observed in the effective bimolecular rate coefficient for CH(3)F addition, and these are consistent with expected trends in the electrostatic binding energies of the adduct ions and measured trends in the standard free energy of addition. HF elimination is the major reaction channel with As(+), while dehydrogenation dominates the reactions of W(+), Os(+), Ir(+), and Pt(+). Sequential F atom transfer is observed with the early-transition-metal cations, with the number of F atoms transferred increasing across the periodic table from two to four, maximizing at four for the group 5 cations Nb(+)(d(4)) and Ta(+)(d(3)s(1)), and stopping at two with V(+)(d(4)). Sequential CH(3)F addition was observed with many atomic cations and all of the metal mono- and multifluoride cations that were formed.

Cations↗
PubMed1998

Kinetic and chemical mechanisms for the effects of univalent cations on the spectral properties of aromatic amine dehydrogenase.

Univalent cations and pH influence the UV-visible absorption spectrum of the tryptophan tryptophylquinone (TTQ) enzyme, aromatic amine dehydrogenase (AADH). Little spectral perturbation was observed when pH was varied in the absence of univalent cations. The addition of alkali metal univalent cations (K+, Na+, Li+, Rb+ or Cs+) to oxidized AADH caused significant changes in its absorption spectrum. The apparent Kd for each cation, determined from titrations of the spectral perturbation, decreased with increasing pH. Transient kinetic studies involving rapid mixing of AADH with cations and pH jump revealed that the rate of the cation-induced spectral changes initially decreased with increasing cation concentration to a minimum value, then increased with increasing cation concentration. A kinetic model was developed to fit these data, determine the true pH-independent Kd values for K+ and Na+, and explain the pH-dependence of the apparent Kd. A chemical reaction mechanism, based on the kinetic data, is presented in which the metallic univalent cation facilitates the chemical modification of the TTQ prosthetic group to form an hydroxide adduct which gives rise to the spectral change. Addition of NH4(+)/NH3 to AADH caused changes in the absorption spectrum which were very different form those caused by addition of the metallic univalent cations. The kinetics of the reaction induced by addition of NH4+/NH3 were also different, being simple saturation kinetics. Another reaction mechanism is proposed for the NH4+/NH3-induced spectral change that involves nucleophilic addition of the unprotonated NH3 to TTQ. The general relevance of these data and models to the physiological reactions of TTQ-dependent enzymes and to the roles of univalent cations in modulating enzyme activity are discussed.

Alcaligenes↗
PubMed2006

Thermodynamic analyses of the specific interaction between two C:C mismatch base pairs and silver (I) cations.

We have already found that a single silver (I) cation specifically binds to a single C:C mismatch base pair in heteroduplex, which increases the melting temperature (T(m)) of heteroduplex involving a single C:C mismatch base pair by about 4 degrees C. Here, to examine the properties of the interaction between two C:C mismatch base pairs and silver (I) cations, we analyzed the effect of silver (I) cations on the thermal stability of heteroduplexes involving two C:C mismatch base pairs. The positions of the two C:C mismatch base pairs in heteroduplex did not significantly affect the magnitude of the increase in T(m) upon addition of silver (I) cation, suggesting that the binding affinity of the first silver (I) cation with one of the two C:C mismatch base pairs and that of the second silver (I) cation with the other of the two mismatch base pairs may be independent of the positions of the two mismatch base pairs. The larger magnitude of the increase in T(m) for the second silver (I) cation binding than that observed for the first silver (I) cation binding suggests that the binding affinity for the second silver (I) cation may be significantly higher than that for the first silver (I) cation. Our results certainly support the idea that addition of the metal cation is a promising strategy for the mismatch base pair detection in the heteroduplex analysis and may eventually lead to progress in SNP genotyping.

Base Pair Mismatch↗
PubMed1984

Studies on cation-induced membrane vesicle aggregation of porcine intestinal brush borders.

Cation specificity and effects of pH and temperature on membrane aggregation of porcine intestinal brush borders were studied in terms of the turbidity change of the membrane suspensions due to the addition of polyvalent cations. Monovalent cations (K+ and Na+) did not induce the membrane aggregation at 5 mM or below. Divalent and trivalent cations induced membrane aggregation even below 0.5 mM in the following orders of effectiveness: Hg2+ much greater than Cd2+ greater than Zn2+ greater than Mn2+ greater than Ca2+ greater than or equal to Ba2+ greater than Sr2+ greater than or equal to Mg2+ and Lu3+ greater than Yb3+ greater than Nd3+ = Er3+ = Tb3+ greater than Ce3+ greater than La3+, respectively. The aggregation of membranes induced by these polyvalent cations was reversible. Membrane aggregation induced by either divalent or trivalent cations followed saturation kinetics with increasing cation concentration and the apparent dissociation constants of these cations for the membranes were estimated to be at 4-6 mM for divalent cations (Ca2+, Mn2+, and Sr2+) and 1-2 mM for trivalent cations (Lu3+, Tb3+, and La3+). Cd2+ and Hg2+ had peculiarly much lower dissociation constants than any other divalent cations tested, being rather comparable to trivalent ones. The membrane aggregation induced by Ca2+, Mn2+, or Sr2+ was independent of pH in the range of 6.6 to 8.0, whereas that induced by Tb3+ or Cd2+ was linearly enhanced with increasing pH, very steeply above pH 7.0. The membrane aggregation induced by Cd2+, Hg2+, or Tb3+ was enhanced steadily with increasing temperature between 15 and 45 degrees C. On the other hand, Ca2+-induced aggregation showed a peak at around 30 degrees C in the temperature dependence profile, still being enhanced above 40 degrees C.

Animals↗
PubMed1996

Ca(2+)-dependent non-selective cation and potassium channels activated by bradykinin in pig coronary artery endothelial cells.

1. Using the cell-attached and inside-out modes of the patch-clamp technique, we studied the Ca(2+)-dependent ionic channels activated by bradykinin in cultured pig coronary artery endothelial cells to further understand electrophysiological events underlying cellular activation. 2. In the cell-attached mode, bradykinin (94 nM) activated two types of Ca(2+)-dependent channels: a high conductance K+ channel (285 pS in high symmetrical K+), whose open state probability was increased by depolarization, and a lower conductance inwardly rectifying non-selective cation channel (44 pS in high symmetrical K+). 3. The 285 pS K+ channel was half-maximally activated by cytosolic Ca2+ levels of 1.6 and 4.5 microM at +10 and -30 mV, respectively. Such local concentrations should be reached in the presence of bradykinin, which induces a mean maximal cytosolic Ca2+ rise of 1.3 microM. 4. The 285 pS K+ channel was inhibited by d-tubocurarine, which acted by reducing the mean open time duration (flickering pattern), finally reducing the channel conductance. 5. Divalent cations such as Ca2+ could flow through the 44 pS non-selective cation channel, with nearly the same permeability (P) as monovalent cations (PK: PNa: PCa = 1:1:0.7). 6. The cation channel appeared to be more sensitive to Ca2+ than the K+ channel, with a half-maximal open probability induced by 0.7 microM Ca2+ on the intracellular side of the membrane. 7. In contrast to the K+ channel, the cation channel mean open time was clearly increased by bradykinin. This effect was delayed compared with the increase in the channel open state probability and was rapidly lost in the inside-out configuration. Caffeine also activated the cation channel but more transiently than bradykinin and without any effect on the open duration. 8. In the absence of extracellular Ca2+, the bradykinin-induced increase in cytosolic free Ca2+ was shortened temporally by 52% and reduced in amplitude by 88%, whereas the bradykinin-induced hyperpolarization was not significantly reduced in amplitude but was shortened by 70%, thus illustrating the major role of Ca2+ influx in endothelial cell activation by bradykinin. 9. We conclude that bradykinin activates two types of Ca(2+)-dependent channels in coronary endothelial cells: a high conductance K+ channel regulated by membrane potential, and an inwardly rectifying cation channel allowing Ca2+ entry, the cation channel being about 6 times more sensitive to Ca2+ than the K+ channel. The increase in cation channel open state probability involves an increase in open number, like the K+ channel, but also involves a rise in channel open duration. Ca2+ entry via cation channels could contribute to increase the cytoplasmic Ca2+ level, activate Ca(2+)-dependent K+ channels, thus triggering membrane hyperpolarization when the endothelial cell is stimulated by a vasoactive agonist such as bradykinin.

Animals↗
PubMed1982

Induction of membranous nephropathy in rabbits by administration of an exogenous cationic antigen.

We examined the role of antigenic electrical charge as a determinant of glomerular immune complex localization in the rabbit. Serum sickness nephritis was induced in groups of New Zealand white rabbits by daily 25-mg intravenous injections of bovine serum albumin (BSA) chemically modified to be cationic (pI > 9.5) or more anionic (pI, 3.5-4.6); an additional group received unmodified native BSA (pI, 4.5-5.1). Factors known to influence immune complex localization, e.g., molecular size of the administered antigen and resulting circulating immune complexes, immunogenicity, and disappearance time from the circulation were examined and found to be similar for both anionic and cationic BSA. Charge modification did increase the nonimmune clearance of cationic and anionic BSA compared with native BSA. Injected cationic BSA was shown in paired label experiments to bind directly to glomeruli compared with native BSA. The renal lesion produced by cationic BSA was markedly different from that found in rabbits given anionic or native BSA. Animals receiving cationic BSA uniformly developed generalized diffuse granular capillary wall deposits of IgG, C3, and BSA detected after 2 wk of injections and increasing until death at 6 wk. Qualitatively similar deposits were produced by the administration of low doses of cationic BSA of only 1 or 10 mg/d. In contrast, the injection of both anionic and native BSA resulted in mesangial deposits at 2 and 4 wk with capillary wall deposits appearing by 6 wk. Ultrastructural examination of animals receiving cationic BSA revealed pure, extensive formation of dense deposits along the lamina rara externa of the glomerular basement membrane whereas such deposits were absent or rare in animals injected with the anionic or native BSA. Albuminuria was significantly greater at 6 wk in the groups receiving cationic BSA with a mean of 280 mg/24 h compared with 53 mg/24 h in the combined groups injected with anionic or native BSA. Blood urea nitrogen values were similar in all groups at 2 and 4 wk but higher in the animals receiving cationic BSA at 6 wk. These experiments describe the reproducible induction of epimembranous immune deposits by administration of an exogenous cationic antigen. They suggest that antigenic charge can play an important role in the pathogenesis of membranous nephropathy by permitting direct glomerular binding of an antigen and predisposing to in situ immune complex formation.

Albuminuria↗
PubMed2006

Microfluidic polymer chip integrated with an ISFET detector for cationic surfactant assay in dental rinses.

A cationic surfactant ion-selective field-effect transistor (cationic surfactant-ISFET) has been developed based on the tetraphenylborate derivative known as sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. The cationic surfactant-ISFET shows an almost Nernstian response to tetradecyldimethylbenzylammonium chloride (Zephiramine) over a concentration range between 1.0 x 10(-6) M and 1.0 x 10(-3) M, with a slope of 58.5 +/- 1.7 mV/decade. The cationic surfactant-ISFET can be used over a range of pH values, between pH 3 and 9. The cationic surfactant-ISFET shows excellent selectivity for Zephiramine over small inorganic cations, but shows similar selectivity for other cationic surfactants, such as hexadecyltrimethylammonium and stearyltrimethylammonium ions. A microfluidic polymer chip was integrated with the cationic surfactant-ISFET, and this was fabricated using polystyrene plates and stainless wires as a template for the channel. Cationic surfactant-ISFETs used in a batch system and microchips integrated with cationic surfactant-ISFETs showed very similar performance in terms of low detection limits, slope sensitivity and the stability of the potential response. The microfluidic polymer chip was then applied to the determination of cationic surfactants in dental rinses.

Calibration↗
PubMed1988

Deoxygenation-induced cation fluxes in sickle cells: relationship between net potassium efflux and net sodium influx.

Deoxygenation-induced cation fluxes in sickle cells were studied by measuring net cation movements in ouabain-treated cells. These deoxy cation fluxes were highly dependent on pH, showing inhibition at pH less than 7 and greater than 8 and a maximum at 7.4-7.5. Activation occurred at oxygen tensions around 40-50 torr and fluxes rose sharply as PO2 fell lower. Deoxy K efflux paralleled deoxy Na influx at pH values between 7 and 8, and at all oxygen tensions. Sickle cells were separated by density on Percol-Stractan gradients. Dense cells had lower deoxy cation fluxes of both Na and K than did lighter cell fractions, but in none of the fractionated populations did deoxy K efflux exceed deoxy Na influx. These data demonstrate that deoxy cation fluxes are activated at physiological pH and oxygen tensions and that there are no conditions of pH and PO2 and no cell populations in which cation fluxes induced by deoxygenation contribute directly to net cation loss in sickle cells. Chloride replacement (with nitrate) did not alter deoxy cation fluxes, and deoxy K efflux did not require the presence of external Na (tetramethylammonium replacement). Thus, deoxy cation fluxes do not have the characteristics of a cation-chloride cotransport or cation countertransport system.

Anemia, Sickle Cell↗
PubMed1993

Effects of competitive sodium-like antagonists on Na,K-ATPase suggest that cation occlusion from the cytoplasmic surface occurs in two steps.

Information on cation occlusion sites of renal NA,K-ATPase has been obtained by comparing the ability of competitive Na-like antagonists (David, P., Mayan, H., Cohen, H., Tal, D. M., and Karlish, S. J. D. (1992) J. Biol. Chem. 267, 1141-1149) with that of transported alkali metal cations to protect against covalent modification and structural perturbations of the protein. Sodium antagonists include p- or m-xylylenebisguanidium, guanidinium ions, and ethylenediamine. Experiments with proteoliposomes reconstituted with Na,K-ATPase demonstrate that p-xylylenebisguanidium has pronounced selectivity for the cytoplasmic surface. Tryptic digestion of Na,K-ATPase leading to "19-kDa membranes," a specifically truncated enzyme with intact cation occlusion sites, requires the presence of alkali metal cations. Sodium antagonists do not protect 19-kDa membranes against further digestion, and occlusion is destroyed. Incubation of 19-kDa membranes at 37 degrees C, in the absence of occluded ions, leads rapidly to loss of ability to occlude rubidium ions. Rubidium, sodium, or other alkali metal cations protect fully, whereas sodium antagonists do not protect against this thermal inactivation. Like the alkali metal cations, sodium antagonists protect Na,K-ATPase and, somewhat less effectively, 19-kDa membranes against inactivation by the carboxyl reagent N,N'-dicyclohexylcarbodiimide. Cation occlusion from the cytoplasmic surface is suggested to occur in two steps. In an initial recognition, either transported cations or sodium antagonists interact with carboxyl groups. The second step is selective for transported cations and involves occlusion of cations (either potassium or sodium ions) and a conformational change to a compact structure, which is resistant to proteolysis and thermal inactivation. Sodium antagonists are sterically hindered from becoming occluded and block Na,K-ATPase activity. Implications for the structural basis of cation specificity of the Na/K pump are discussed.

Animals↗
PubMed2004

Effect of the exchangeable cations on the spectral properties of methylene blue in clay dispersions.

Adsorption of a cationic dye, methylene blue (MB), on the surface of montmorillonite leads to the molecular aggregation of dye cations, reflected by significant changes of dye optical properties. Montmorillonite samples, saturated with various inorganic cations (mono-, bi-, and trivalent, including those of transition metals), were used. Influence of the exchangeable cations on the MB aggregation was tested. Various properties of cations were considered (charge, diameter, acidity, hydration energies). Both direct and potential indirect effects of the cations were taken into account, such as salting-out effect, influence of the ions on solvent polarity, influence on swelling, colloid properties of montmorillonite dispersions, cation hydration properties, hydrolysis, and interaction of the cations with the clay surface. The spectra of MB in dispersions of montmorillonite saturated with NH4+, K+, Rb+, and Cs+ were significantly different from those of other reaction systems. Direct association between large monovalent cations and basal oxygen atoms of silicate probably leads to a partial fixation of the cations, which affects the ion exchange reaction and dye aggregation. Thus, the presence of large monovalent cations leads to the formation of fewer ordered H-aggregates in favor of monomers and aggregates of lower size. In these cases, dye species absorbing light of low energies also appeared in significant amounts and were assigned to J-aggregates, characterized by a head-to-tail intermolecular association.

Journal Article↗
PubMed1997

Toxicity and immunomodulatory activity of liposomal vectors formulated with cationic lipids toward immune effector cells.

Liposomal vectors formulated with cationic lipids (cationic liposomes) and fusogenic dioleoylphosphatidylethanolamine (DOPE) have potential for modulating the immune system by delivering gene or antisense oligonucleotide inside immune cells. The toxicity and the immunoadjuvant activity of cationic liposomes containing nucleic acids toward immune effector cells has not been investigated in detail. In this report, we have evaluated the toxicity of liposomes formulated with various cationic lipids towards murine macrophages and T lymphocytes and the human monocyte-like U937 cell line. The effect of these cationic liposomes on the synthesis of two immunomodulators produced by activated macrophages, nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha), has also been determined. We have found that liposomes formulated from DOPE and cationic lipids based on diacyltrimethylammonium propane (dioleoyl-, dimyristoyl-, dipalmitoyl-, disteroyl-: DOTAP, DMTAP, DPTAP, DSTAP) or dimethyldioctadecylammonium bromide (DDAB) are highly toxic in vitro toward phagocytic cells (macrophages and U937 cells), but not towards non-phagocytic T lymphocytes. The rank order of toxicity was DOPE/DDAB > DOPE/DOTAP > DOPE/DMTAP > DOPE/DPTAP > DOPE/DSTAP. The ED50's for macrophage toxicity were < 10 nmol/ml for DOPE/DDAB, 12 nmol/ml for DOPE/DOTAP, 50 nmol/ml for DOPE/DMTAP, 400 nmol/ml for DOPE/DPTAP and > 1000 nmol/ml for DOPE/DSTAP. The incorporation of DNA (antisense oligonucleotide or plasmid vector) into the cationic liposomes marginally reduced their toxicity towards macrophages. Although toxicity was observed with cationic lipids alone, it was clearly enhanced by the presence of DOPE. The replacement of DOPE by dipalmitoylphosphatidylcholine (DPPC) significantly reduced liposome toxicity towards macrophages, and the presence of dipalmitoylphosphatidylethanolamine-PEG2000 (DPPE-PEG2000: 10 mol%) in the liposomes completely abolished this toxicity. Cationic liposomes, irrespective of their DNA content, downregulated NO and TNF-alpha synthesis by lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma)-activated macrophages. The replacement of DOPE by DPPC, or the addition of DPPE-PEG2000, restored NO and TNF-alpha synthesis by activated macrophages. Since macrophages constitute the major site of liposome localization after parenteral administration and play an important role in the control of the immune system, cationic liposomes should be used with caution to deliver gene or antisense oligonucleotide to mammalian cells. Cationic lipids show in vitro toxicity toward phagocytic cells and inhibit in vitro and in situ NO and TNF-alpha production by activated macrophages.

Animals↗
PubMed2003

Impact of multiple cation-pi interactions upon calix[4]arene substrate binding and specificity.

The cation-pi interaction influence on the conformation and binding of calix[4]arenes to alkali-metal cations has been studied using a dehydroxylated model. The model allows for the separation of cooperative cation-pi and electrostatic forces commonly found in the binding motifs found in calixarene complexes. Starting from the four well-known calix[4]arene conformations, six conformers for this dehydroxylated model (cone, partial cone, flattened cone, chair, 1,2-alternate, and 1,3-alternate) have been characterized by geometry optimization and frequency analysis using the Becke three-parameter exchange functional with the nonlocal correlation functional of Lee, Yang, and Parr and the 6-31G(d) basis set. Without the stabilization provided by the hydroxyl hydrogen bonds in calix[4]arene, neither the cone nor the 1,2-alternate conformation is computed to be a ground-state structure. The partial cone, flattened cone, chair, and 1,3-alternate conformers have been identified as ground-state structures in a vacuum, with the partial cone and the 1,3-alternate as the lowest energy minima in the aromatic model. The C(4)(v)() cone conformation is found to be a transition structure separating the flattened cone (C(2)(v)()) conformers. The energetic and structural preferences of the calix[4]arene model change dramatically when it is bound to Li(+), Na(+), and K(+). The number of pi-faces, the positioning of these pi-faces with respect to the cations, and the nature of the cation were studied as factors in the binding strength. A detailed study of the distances and angles between the aromatic ring centroids and the cations reveals the energetic advantages of multiple weak cation-pi interactions. The geometries are often far from the optimal cation-pi interaction in which the cation approaches in a perpendicular path the aromatic ring center, where the quadrupole moment is strongest. The results reveal that multiple weaker nonoptimal cation-pi interactions contribute significantly to the overall binding strength. This theoretical analysis underscores the importance of neighboring aromatic faces and provides new insight into the significance of cation-pi binding, not only for calix[4]arenes, but also for other supramolecular and biological systems.

Journal Article↗
PubMed2006

Gas-phase reactions of carbon dioxide with atomic transition-metal and main-group cations: room-temperature kinetics and periodicities in reactivity.

The chemistry of carbon dioxide has been surveyed systematically with 46 atomic cations at room temperature using an inductively-coupled plasma/selected-ion flow tube (ICP/SIFT) tandem mass spectrometer. The atomic cations were produced at ca. 5500 K in an ICP source and allowed to cool radiatively and to thermalize by collisions with Ar and He atoms prior to reaction downstream in a flow tube in helium buffer gas at 0.35 +/- 0.01 Torr and 295 +/- 2 K. Rate coefficients and products were measured for the reactions of first-row atomic ions from K(+) to Se(+), of second-row atomic ions from Rb(+) to Te(+) (excluding Tc(+)), and of third-row atomic ions from Cs(+) to Bi(+). CO(2) was found to react in a bimolecular fashion by O atom transfer only with 9 early transition-metal cations: the group 3 cations Sc(+), Y(+), and La(+), the group 4 cations Ti(+), Zr(+), and Hf(+), the group 5 cations Nb(+) and Ta(+), and the group 6 cation W(+). Electron spin conservation was observed to control the kinetics of O atom transfer. Addition of CO(2) was observed for the remaining 37 cations. While the rate of addition was not measurable some insight was obtained into the standard free energy change, DeltaG(o), for CO(2) ligation from equilibrium constant measurements. A periodic variation in DeltaG(o) was observed for first row cations that is consistent with previous calculations of bond energies D(0)(M(+)-CO(2)). The observed trends in D(0) and DeltaG(o) are expected from the variation in electrostatic attraction between M(+) and CO(2) which follows the trend in atomic-ion size and the trend in repulsion between the orbitals of the atomic cations and the occupied orbitals of CO(2). Higher-order CO(2) cluster ions with up to four CO(2) ligands also were observed for 24 of the atomic cations while MO(2)(+) dioxide formation by sequential O atom transfer was seen only with Hf(+), Nb(+), Ta(+), and W(+).

Journal Article↗
PubMed1998

Interactions between P-glycoprotein substrates and other cationic drugs at the hepatic excretory level.

1. In the present study it was tested whether known P-glycoprotein (P-gp) substrates/MDR reversal agents interact with small (type 1) and bulky (type 2) cationic drugs at the level of biliary excretion in the rat isolated perfused liver model (IPRL). The studies were performed with model compounds tri-n-butylmethylammonium (TBuMA) (a relatively small type 1 organic cation), rocuronium (Roc) (a bulky type 2 organic cation) and the classical P-gp substrate doxorubicin (Dox). 2. Inhibitors were given in a 4 fold molar excess to the substrate studied. To minimize an interaction of the substrates at the hepatic uptake level, the competing compounds were added when over 55% to 85% of the administered dose of the model compounds had been removed from the perfusate and taken up by the liver. 3. We found a mutual interaction between TBuMA and procainamidethobromide (PAEB), both type 1 cationic compounds during biliary excretion. Interestingly, type 2 compounds, such as rocuronium, clearly inhibited type 1 cationic drugs as well as Dox secretion into bile, whereas type 1 compounds did not significantly inhibit type 2 drug excretion into bile. The type 1 cations PAEB and TBuMA only moderately inhibited Dox biliary excretion. Dox did not inhibit the biliary excretion of the type 2 agent rocuronium whereas rocuronium reduced Dox biliary excretion by 50% compared to controls. 4. MDR substrates/reversal agents like verapamil, quinine, quinidine and vinblastine strongly reduced both type 1 and type 2 organic cation excretion into bile. Dox secretion into bile was also profoundly reduced by these drugs, vinblastine being the most potent inhibitor in general. 5. The lack of mutual inhibition observed in some combinations of substrates may indicate that major differences in affinity of the substrates for a single excretory system exist. Alternatively, multiple organic cation transport systems with separate substrate specificities may be involved in the biliary excretion of amphiphilic drugs. Furthermore, the present study revealed a clear positive correlation between the lipophilicity of the potential inhibitors studied and their respective inhibitory activity on the biliary excretion of the model drugs investigated. 6. Our data are compatible with a potential involvement of P-glycoprotein in the hepatobiliary excretion of doxorubicin as well as of some type 1 and type 2 organic cations. Furthermore we postulate that the hydrophobic properties of the amphiphilic cationic drugs studied play a crucial role in the accommodation of these agents by P-glycoprotein and/or other potential cationic drug carrier proteins in the canalicular membrane.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

A unique coordination environment for an ion: EXAFS studies and bond valence model approach of the encapsulated cation in the Preyssler anion.

X-Ray absorption spectroscopy was used to probe the coordination of different encrypted cations in the Preyssler anions [M(n+)P5W(30)O(110)]((15-n)-)(M(n+)= Sr2+, Am3+, Eu3+, Sm3+, Y3+, Th4+, U4+ in decreasing order of ionic radius, IR), hereafter abbreviated [M(n+)PA](15-n)-. The increase of the M-W distance and the decrease of the M-P distance with increasing M ionic radius reveal that the M cation is displaced along the C5 axis within the Preyssler cavity. The slight change (0.07 A) of the M-O distance that does not correspond to the IR difference of 0.27 A confirms that the cavity retains its rigidity upon cation substitution. Geometric modeling of the encapsulated cation in the channel was performed for comparison to the EXAFS results. The position of the cation in the cavity was calculated as well as the M-O10, -W5 and -P5 distances. This modeling confirms the cation displacement toward the center of the Preyssler anion as the cation size increases, which is understood in terms of the non-homogenous electrostatic potential present within the cavity. The bond valence model approach was applied to obtain experimental bond valences. Only the bond valence sum (BVS) of Am3+ is close to its actual charge. Sums smaller than the actual valences of the +3 and +4 ions (2.39-2.63 for +3 cations, Y, Sm, Eu; 3.17 and 3.38 for +4 cations, U and Th, respectively) were obtained, and a larger sum (2.89) was obtained for Sr2+. The deviations from the formal M sums of the encapsulated ions are attributed to the rigidity of the Preyssler framework. The tendency toward coordinative unsaturation for electroactive cations, such as Eu3+, is thought to be the driving force for facile reduction. Unlike other inorganic chelating ligands, the Preyssler anion provides a unique redox system to stabilize an electroactive cation in a low oxidation state.

Journal Article↗
PubMed2000

Permeation of large tetra-alkylammonium cations through mutant and wild-type voltage-gated sodium channels as revealed by relief of block at high voltage.

Many large organic cations are potent blockers of K(+) channels and other cation-selective channels belonging to the P-region superfamily. However, the mechanism by which large hydrophobic cations enter and exit the narrow pores of these proteins is obscure. Previous work has shown that a conserved Lys residue in the DEKA locus of voltage-gated Na(+) channels is an important determinant of Na(+)/K(+) discrimination, exclusion of Ca(2+), and molecular sieving of organic cations. In this study, we sought to determine whether the Lys(III) residue of the DEKA locus interacts with internal tetra-alkylammonium cations (TAA(+)) that block Na(+) channels in a voltage-dependent fashion. We investigated block by a series of TAA(+) cations of the wild-type rat muscle Na(+) channel (DEKA) and two different mutants of the DEKA locus, DEAA and DERA, using whole-cell recording. TEA(+) and larger TAA(+) cations block both wild-type and DEAA channels. However, DEAA exhibits dramatic relief of block by large TAA(+) cations as revealed by a positive inflection in the macroscopic I-V curve at voltages greater than +140 mV. Paradoxically, relief of block at high positive voltage is observed for large (e.g., tetrapentylammonium) but not small (e.g., TEA(+)) symmetrical TAA(+) cations. The DEKA wild-type channel and the DERA mutant exhibit a similar relief-of-block phenomenon superimposed on background current rectification. The results indicate: (a) hydrophobic TAA(+) cations with a molecular diameter as large as 15 A can permeate Na(+) channels from inside to outside when driven by high positive voltage, and (b) the Lys(III) residue of the DEKA locus is an important determinant of inward rectification and internal block in Na(+) channels. From these observations, we suggest that hydrophobic interfaces between subunits, pseudosubunits, or packed helices of P-region channel proteins may function in facilitating blocker access to the pore, and may thus play an important role in the blocking and permeation behavior of large TAA(+) cations and potentially other kinds of local anesthetic molecules.

Animals↗
PubMed1986

Only the initial binding of cationic immune complexes to glomerular anionic sites is mediated by charge-charge interactions.

The role of charge-charge interactions between cationic immune complexes and the anionic sites on the glomerular basement membrane was examined. For this purpose, soluble immune complexes at fivefold antigen excess were prepared with human serum albumin and cationized rabbit antibodies to this protein. When unrelated cationic proteins, protamine sulfate or cationized rabbit serum albumin, were given 1 min before the cationized immune complexes, glomerular immune deposits did not form. Cationic immune complexes allowed to deposit in glomeruli could readily be displaced by protamine sulfate or cationized rabbit serum albumin injected 1 min after the immune complexes. If the same cationic molecules were injected 1 hr after the immune complexes, the complexes could not be displaced from glomeruli. In contrast, cationic complexes that were deposited in glomeruli in the presence of a very high degree of antigen excess in circulation to prevent their condensation into larger complexes in glomeruli were readily displaced at 1 min and 1 hr with protamine sulfate or with cationized rabbit serum albumin. On the basis of these results, we concluded that the initial binding of cationic immune complexes to glomeruli occurs by charge-charge interactions. Once the immune complexes in glomeruli condense to larger deposits, forces other than charge-charge interactions are responsible for their retention in glomeruli.

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