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At least 199 records · Page 11Linked to original sources
PubMed1989

Phase synchronization of an ion ensemble by frequency sweep excitation in Fourier transform ion cyclotron resonance.

The Fourier transform ion cyclotron resonance (FT-ICR) signal is produced by the coherent motion of a population of ions. The ability to produce a well-defined ion packet by excitation of an initially random ion ensemble is a major limiting factor of high mass FT-ICR. Ions must be both resonant and in phase with the applied radio frequency excitation field to be accelerated to radii suitable for detection by FT-ICR. Synchronization of the phase angles of an ensemble of ions occurs by off-resonant acceleration during frequency swept excitation. Results from computer-simulated ion trajectories suggest that phase synchronization of the ion packet prior to resonant excitation results in better spatial definition of the ion ensemble.

Computer Simulation↗
PubMed2003

Ion sensing and inhibition studies using the transmembrane ion channel peptide gramicidin A entrapped in sol-gel-derived silica.

The development of new, targeted drugs relies heavily on innovative technologies that allow for high-throughput screening of drug libraries against biologically relevant targets, particularly membrane-associated receptors. Therefore, immobilization of natural receptors is of the utmost importance to allow for screening of small molecule libraries. Herein, we describe the immobilization of liposomes containing the transmembrane peptide ion-channel gramicidin A into sol-gel-derived silicate materials. Steady-state fluorescence measurements of the intrinsic tryptophan residues of reconstituted gramicidin A in phospholipid vesicles consisting of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) were obtained in solution and following entrapment in diglyceryl silane (DGS)-derived silicate to examine the effects of entrapment on the conformation of the ion channel. Only minor deviations were observed in the fluorescence properties of gramicidin following entrapment in DGS-derived silicate. DOPC vesicles containing a 50 microM internal solution of the potential sensitive fluorescent dye safranine O were used to study ion flux through the membrane ion channel. The dependence of ion flux on both ion concentration and amount of gramicidin embedded in the membrane were examined before and after entrapment in sol-gel-derived silicate. It was found that ion channel activity upon entrapment in DGS-derived silicate mirrored very closely that observed in solution. Moreover, the ability to inhibit ion flux through gramicidin A due to blockage by calcium ions was retained after the immobilization procedure. The implications for development of drug-screening and -sensing platforms are discussed.

Anti-Bacterial Agents↗
PubMed1998

An ion funnel interface for improved ion focusing and sensitivity using electrospray ionization mass spectrometry.

To improve upon the already impressive sensitivity achievable with electrospray ionization sources, a novel electrohydrodynamic ion funnel interface has been developed and implemented with a triple-quadrupole mass spectrometer. The ion funnel interface effectively consists of a series of ring electrodes of increasingly small internal diameters to which rf and dc electric potentials are coapplied. In the 1-10-Torr pressure range, the electric fields cause the collisionally damped ions to be more effectively focused and transmitted as a collimated ion beam. This paper describes the ion funnel design and presents an evaluation of its performance using a triple-quadrupole mass spectrometer. Ion transmission and m/z discriminating parameters (resulting in both effective low- and high-m/z cutoffs) are presented based upon both ion current measurements and mass spectra. Electrospray ionization mass spectra of selected protein solutions demonstrated well over 1 order of magnitude increase in signal relative to that of the instrument operated in its standard (inlet capillary-skimmer) configuration under similar conditions. The present results suggest that it will be feasible to realize close to 100% ion transmission efficiency for analytically relevant ions through the electrospray ionization interface and into the mass analyzer.

Animals↗
PubMed2006

Field asymmetric waveform ion mobility spectrometry studies of proteins: Dipole alignment in ion mobility spectrometry?

Approaches to separation and characterization of ions based on their mobilities in gases date back to the 1960s. Conventional ion mobility spectrometry (IMS) measures the absolute mobility, and field asymmetric waveform IMS (FAIMS) exploits the difference between mobilities at high and low electric fields. However, in all previous IMS and FAIMS experiments ions experienced an essentially free rotation; thus the separation was based on the orientationally averaged cross-sections Omega(avg) between ions and buffer gas molecules. Virtually all large ions are permanent electric dipoles that will be oriented by a sufficiently strong electric field. Under typical FAIMS conditions this will occur for dipole moments >400 D, found for many macroions including most proteins above approximately 30 kDa. Mobilities of aligned dipoles depend on directional cross-sections Omega(dir) (rather than Omega(avg)), which should have a major effect on FAIMS separation parameters. Here we report the FAIMS behavior of electrospray-ionization-generated ions for 10 proteins up to approximately 70 kDa. Those above 29 kDa exhibit a strong increase of mobility at high field, which is consistent with predicted ion dipole alignment. This effect expands the useful FAIMS separation power by an order of magnitude, allowing separation of up to approximately 10(2) distinct protein conformers and potentially revealing information about Omega(dir) and ion dipole moment that is of utility for structural characterization. Possible approaches to extending dipole alignment to smaller ions are discussed.

Electrochemistry↗
PubMed1975

Spectator-ion effect on the passage of ions through membranes.

In this paper, we investigate the interplay between geometric and dielectric factors in influencing the image force acting on an ion passing through a membrane, for a system having the approximate dimensions of Escherichia coli. We also study the effect of one ion in a membrane on the passage of a second ion through the membrane, by calculating the radial and angular forces experienced by the second ion due to the presence of the "spectator ion." Our conclusions follow from numerical studies on expressions obtained by solving (exactly) Laplace's equation for the model assumed in this paper. The conclusions are: (i) small changes in the dielectric constant of the membrane are far more significant in determining the image force acting on an ion in a membrane than dramatic changes in the dielectric character of the regions interior and/or exterior to the cell; (ii) a spectator ion in a membrane situated near a boundary may influence in a significant way the passage of a second ion through the middle third of the membrane. We suggest that this latter result should be taken into account in discussing the mechanism of ion migration across membranes.

Biological Transport, Active↗
PubMed2004

Initial pH, base deficit, lactate, anion gap, strong ion difference, and strong ion gap predict outcome from major vascular injury.

OBJECTIVE: This study determines whether acid-base data obtained in the emergency department correlate with outcome from major vascular injury. DESIGN: Observational, retrospective record review of trauma patients requiring vascular repair (torso or extremity, January 1988 to December 1997). Data included age, Injury Severity Score, injury mechanism, survival, laboratory profiling, calculated anion gap, strong ion difference, and strong ion gap. Patients were divided into survivors and nonsurvivors with comparison by Student's t-test; significance was assumed for p < or = .05. Multivariate logistic regression was used for further analysis of univariate predictors of mortality, and receiver operator characteristic curves were generated for mortality from each variable. SETTING: Urban level I trauma facility. PATIENTS: Trauma patients requiring vascular repair of torso or extremity injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Both nonsurvivors (n = 64) and survivors (n = 218) were similar with respect to age (31 +/- 9 vs. 31.5 +/- 10.5, p = 0.15) and injury mechanics (81% penetrating in survivors vs. 83% penetrating in nonsurvivors, p = .71). Non-survivor Injury Severity Score exceeded that of survivors (27.5 +/- 7.8 vs. 12.4 +/- 9.4, p < .001). Nonsurvivor pH (7.06 +/- 0.15 vs. 7.34 +/- 0.08, p < .001) and apparent strong ion difference (31.38 +/- 4.39 vs. 37.53 +/- 3.86, p < .001) were significantly lower, whereas nonsurvivor standard base excess (-17.9 +/- 5.1 vs. -2.9 +/- 4.4 mEq/L, p < .001), lactate (11.1 +/- 3.6 vs. 3.6 +/- 1.5 mmol/L, p < .001), anion gap (28.2 +/- 4.1 vs. 15.6 +/- 3.1, p < .001), and strong ion gap (10.8 +/- 3.2 vs. 2.4 +/- 1.8, p < .001) were higher. All but one nonsurvivor had initial emergency department pH < or = 7.26, standard base excess < or = -7.3 mEq/L, lactate > or = 5 mmol/L, and strong ion gap > or = 5 mEq/L. All of the acid-base descriptors were strongly associated with outcome, but the strong ion gap discriminated most strongly with an area under the receiver operator characteristic of 0.991 (95% confidence interval, 0.972-0.998). CONCLUSIONS: The initial emergency department acid-base variables of pH, base deficit, lactate, anion gap, apparent strong ion difference, and strong ion gap discriminate survivors from non-survivors of major vascular injury. The strong ion gap is most strongly predictive of mortality following major vascular trauma.

Acid-Base Equilibrium↗
PubMed1980

Diffusible ion localization by ion microscopy: a comparison of chemically prepared and fast-frozen, freeze-dried, unfixed liver sections.

The necessity of low temperature preparative procedures for diffusible ion localization using the ion microscope has been established with rat liver as the test material. Using conventional fixation procedures, significant ion loss and redistribution were observed which exceeded the 1 micrometer lateral resolution of the direct imaging ion microanalyser. The compositional morphology evidenced in chemically prepared versus fast-frozen, freeze-dried, unfixed material was compared and evaluated in terms of ion retention, ion redistribution and morphological integrity. A mass spectral analysis of both preparations has been presented and discussed with regard to spectral interferences and elemental sensitivities. Ion images of sodium and potassium were recorded for chemically prepared liver sections and compared with the ion distributions obtained for unfixed, fast-frozen, freeze-dried 1 micrometer thick sections. The magnitude of ion loss during preparation of samples removed at different stages in the course of chemical processing was determined by atomic absorption and flame emission spectrophotometry.

Animals↗
PubMed2005

Physical interaction and functional coupling between ACDP4 and the intracellular ion chaperone COX11, an implication of the role of ACDP4 in essential metal ion transport and homeostasis.

Divalent metal ions such as copper, manganese, and cobalt are essential for cell development, differentiation, function and survival. These essential metal ions are delivered into intracellular domains as cofactors for enzymes involved in neuropeptide and neurotransmitter synthesis, superoxide metabolism, and other biological functions in a target specific fashion. Altering the homeostasis of these essential metal ions is known to connect to a number of human diseases including Alzheimer disease, amyotrophic lateral sclerosis, and pain. It remains unclear how these essential metal ions are delivered to intracellular targets in mammalian cells. Here we report that rat spinal cord dorsal horn neurons express ACDP4, a member of Ancient Conserved Domain Protein family. By screening a pretransformed human fetal brain cDNA library in a yeast two-hybrid system, we have identified that ACDP4 specifically interacts with COX11, an intracellular metal ion chaperone. Ectopic expression of ACDP4 in HEK293 cells resulted in enhanced toxicity to metal ions including copper, manganese, and cobalt. The metal ion toxicity became more pronounced when ACDP4 and COX11 were co-expressed ectopically in HEK293 cells, suggesting a functional coupling between them. Our results indicate a role of ACDP4 in metal ion homeostasis and toxicity. This is the first report revealing a functional aspect of this ancient conserved domain protein family. We propose that ACDP is a family of transporter protein or chaperone proteins for delivering essential metal ions in different mammalian tissues. The expression of ACDP4 on spinal cord dorsal horn neurons may have implications in sensory neuron functions under physiological and pathological conditions.

Animals↗
PubMed1993

Surface-independent acceleration of factor XII activation by zinc ions. I. Kinetic characterization of the metal ion rate enhancement.

The effect of zinc ions (Zn(II)) on the activation of factor XII in the absence of a procoagulant surface was investigated by initial velocity kinetic studies at I = 0.15, pH 7.4, and 25 degrees C. Zinc ions at concentrations greater than 160 microM potentiated 99-fold the kcat/KM for the activation of factor XII by kallikrein and, at an optimum concentration of 110 microM, accelerated 140-fold the apparent kcat/KM for factor XII autoactivation. High molecular weight kininogen had no effect on either metal-potentiated reaction. Analysis of the factor XII concentration dependence of initial activation rates revealed that Zn(II), at levels that saturate the effect, accelerates kallikrein activation of factor XII by lowering KM (from 52 to 7.3 microM) and raising kcat (from 2.6 to 31 min-1). For the autocatalytic activation reaction of factor XII in the presence of optimal Zn(II), apparent KM and kcat values of 2.4 microM and 0.041 min-1, respectively, were determined, but these parameters were not resolvable in the absence of the metal ion. Zinc ions minimally affected kallikrein enzymatic activity and inhibited factor XIIa enzymatic activity with KI values of 20-40 microM, suggesting that the rate-enhancing effects of the metal ion are due to interactions with the substrate (factor XII) rather than with the enzyme. The Zn(II) inhibition of factor XIIa enzymatic activity accounted for a decreased Zn(II) enhancement of factor XII autoactivation at high metal ion concentrations (> 110 microM). The Zn(II) concentration dependence of the acceleration of factor XII activation reactions were sigmoid and characterized by Hill coefficients of 3.3-4.3, suggesting that cooperative binding of at least four zinc ions to factor XII was responsible for the Zn(II) potentiating effect. The Zn(II) enhancement of the rates of factor XII activation decreased both above and below pH 7.4 with midpoint pH values of 6.5-7.0 and 8.0, consistent with histidine and possibly water ligands mediating Zn(II) binding to the protein. Despite an apparent weaker binding of Zn(II) to factor XII at pH 6.5, indistinguishable maximum accelerating effects of the metal ion were observed at saturation at this pH, indicating that the increased positive charge of factor XII resulting from protonation at the lower pH did not mimic the effect of Zn(II) binding. These results imply that zinc ions induce a conformational change in factor XII that makes it a better substrate for its enzyme activators.

Factor XII↗
PubMed2003

Metal ion effects on ion channel gating.

Metal ions affect ion channels either by blocking the current or by modifying the gating. In the present review we analyse the effects on the gating of voltage-gated channels. We show that the effects can be understood in terms of three main mechanisms. Mechanism A assumes screening of fixed surface charges. Mechanism B assumes binding to fixed charges and an associated electrostatic modification of the voltage sensor. Mechanism C assumes binding and an associated non electrostatic modification of the gating. To quantify the non-electrostatic effect we introduced a slowing factor, A. A fourth mechanism (D) is binding to the pore with a consequent pore block, and could be a special case of Mechanisms B or C. A further classification considers whether the metal ion affects a single site or multiple sites. Analysing the properties of these mechanisms and the vast number of studies of metal ion effects on different voltage-gated on channels we conclude that group 2 ions mainly affect channels by classical screening (a version of Mechanism A). The transition metals and the Zn group ions mainly bind to the channel and electrostatically modify the gating (Mechanism B), causing larger shifts of the steady-state parameters than the group 2 ions, but also different shifts of activation and deactivation curves. The lanthanides mainly bind to the channel and both electrostatically and non-electrostatically modify the gating (Mechanisms B and C). With the exception of the ether-à-go-go-like channels, most channel types show remarkably similar ion-specific sensitivities.

Animals↗
PubMed2003

TRPM7 provides an ion channel mechanism for cellular entry of trace metal ions.

Trace metal ions such as Zn(2+), Fe(2+), Cu(2+), Mn(2+), and Co(2+) are required cofactors for many essential cellular enzymes, yet little is known about the mechanisms through which they enter into cells. We have shown previously that the widely expressed ion channel TRPM7 (LTRPC7, ChaK1, TRP-PLIK) functions as a Ca(2+)- and Mg(2+)-permeable cation channel, whose activity is regulated by intracellular Mg(2+) and Mg(2+).ATP and have designated native TRPM7-mediated currents as magnesium-nucleotide-regulated metal ion currents (MagNuM). Here we report that heterologously overexpressed TRPM7 in HEK-293 cells conducts a range of essential and toxic divalent metal ions with strong preference for Zn(2+) and Ni(2+), which both permeate TRPM7 up to four times better than Ca(2+). Similarly, native MagNuM currents are also able to support Zn(2+) entry. Furthermore, TRPM7 allows other essential metals such as Mn(2+) and Co(2+) to permeate, and permits significant entry of nonphysiologic or toxic metals such as Cd(2+), Ba(2+), and Sr(2+). Equimolar replacement studies substituting 10 mM Ca(2+) with the respective divalent ions reveal a unique permeation profile for TRPM7 with a permeability sequence of Zn(2+) approximately Ni(2+) >> Ba(2+) > Co(2+) > Mg(2+) >/= Mn(2+) >/= Sr(2+) >/= Cd(2+) >/= Ca(2+), while trivalent ions such as La(3+) and Gd(3+) are not measurably permeable. With the exception of Mg(2+), which exerts strong negative feedback from the intracellular side of the pore, this sequence is faithfully maintained when isotonic solutions of these divalent cations are used. Fura-2 quenching experiments with Mn(2+), Co(2+), or Ni(2+) suggest that these can be transported by TRPM7 in the presence of physiological levels of Ca(2+) and Mg(2+), suggesting that TRPM7 represents a novel ion-channel mechanism for cellular metal ion entry into vertebrate cells.

Animals↗