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PubMed2006

Zinquin identifies subcellular compartmentalization of zinc in cortical neurons. Relation to the trafficking of zinc and the mitochondrial compartment.

Zinquin (Zn(2+) selective fluorophore), when used to visualize intracellular Zn(2+), typically shows brightly fluorescent perinuclear endosome-like structures, presumably identifying Zn(2+) containing organelles. In this study, zinquin identified numerous and widespread sites of Zn(2+) compartmentalization in primary cultures of embryonic rat cortical neurons. Nuclear fluorescence, however, was absent. We labeled neuronal mitochondria with MitoTracker Green in the presence of zinquin and show that the fluorescent patterns of MitoTracker Green and zinquin were distinct and clearly different in both the perinuclear region and in processes. The mitochondrial compartment was much larger than the sum of the areas of zinquin fluorescence, as indicated by the small amount (<10% MitoTracker Green over zinquin) of overlap of MitoTracker Green on zinquin. Zinquin fluorescence was unaffected by carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) treatment. The zinquin fluorescent objects were generally spherical in shape with a average diameter of about 0.6 mum. Most fluorescent objects, nearly two thirds on average, appeared to be docked, but both anterograde and retrograde movements were observed by time lapse image analysis. Although some fluorescent objects moved as much as 1 mum in 5 min, typical movements were smaller, usually 0.5 mum or less. Colchicine treatment caused striking aggregation of MitoTracker Green most noticeable in the perinuclear region. Zinquin fluorescence similarly showed reduced distribution throughout the cytoplasm, suggesting that zinquin fluorescent structures were associated with microtubules. Treatment with cytochalasin D had little noticeable effect on either the pattern of zinquin and MitoTracker Green fluorescence or their coincidence. Thus, numerous Zn(2+) sequestering organelles/structures are present in perinuclear regions and processes of cultured neurons and are sometimes found coincident with mitochondria. We demonstrated real time trafficking of sequestered Zn(2+), using zinquin fluorescence, apparently associated with an endosome-like compartment or protein complexes in the cytosol.

Analysis of Variance↗

PubMed2004

A computer software for simulating single-compartmental model of neurons.

In this paper, a new computer software package, Yalzer, is introduced for simulating single-compartmental model of neurons. Passive or excitable membranes with voltage-gated ion channels can be modeled, and current clamp and voltage clamp experiments can be simulated. In the Yalzer, first-order differential equations used to define the dynamics of the gate variables and the membrane potential are solved by two separate integration methods with variable time steps: forward Euler and exponential Euler methods. Outputs of the simulation are shown on a spreadsheet template for allowing flexible data manipulation and can be graphically displayed. The user can define the model in detail, and examine the excitability of the model and the dynamics of voltage-gated ion channels. The software package addresses to ones who want to run simple simulations of neurons without need to any programming language skills or expensive software. It can also be used for educational purposes.

Computer Simulation↗

PubMed2005

Estimation of pharmacokinetic parameters from non-compartmental variables using Microsoft Excel.

This study was conducted to develop a method, termed 'back analysis (BA)', for converting non-compartmental variables to compartment model dependent pharmacokinetic parameters for both one- and two-compartment models. A Microsoft Excel spreadsheet was implemented with the use of Solver and visual basic functions. The performance of the BA method in estimating pharmacokinetic parameter values was evaluated by comparing the parameter values obtained to a standard modelling software program, NONMEM, using simulated data. The results show that the BA method was reasonably precise and provided low bias in estimating fixed and random effect parameters for both one- and two-compartment models. The pharmacokinetic parameters estimated from the BA method were similar to those of NONMEM estimation.

Computer Simulation↗

PubMed2005

Regulation of protein compartmentalization expands the diversity of protein function.

Proteins destined for the secretory pathway are translocated into the endoplasmic reticulum (ER) by signal sequences that vary widely in their functional properties. We have investigated whether differences in signal sequence function have been exploited for cellular benefit. A cytosolic form of the ER chaperone calreticulin was found to arise by an aborted translocation mechanism dependent on its signal sequence and factors in the ER lumen and membrane. A signal sequence that functions independently of these accessory translocation factors selectively eliminated cytosolic calreticulin. In vivo replacement of endogenous calreticulin with a constitutively translocated form influenced glucocorticoid receptor-mediated gene activation without compromising chaperone activity in the ER. Thus, in addition to its well-established ER lumenal functions, calreticulin has an independent role in the cytosol that depends critically on its inefficient compartmentalization. We propose that regulation of protein translocation represents a potentially general mechanism for generating diversity of protein function.

Amino Acid Sequence↗

PubMed2005

Biological factors influencing tissue compartmentalization of trace metals in the deep-sea hydrothermal vent bivalve Bathymodiolus azoricus at geochemically distinct vent sites of the Mid-Atlantic Ridge.

In this study, we investigated on concentrations of trace metals (Al, Cd, Mn, Co, and Hg) in the hydrothermal bivalve Bathymodiolus azoricus, a dominant species at most vent sites along the Mid-Atlantic Ridge (MAR), and in its endosymbiont bacteria and commensal parasite Branchipolynoe seepensis. Comparison of our results with data from the literature on non-hydrothermal bivalves suggests lack of "extreme" uptake of trace metals by B. azoricus, except for Hg concentration which exceeded manyfold previously reported values. Mussels collected from three geochemically distinct vent sites, Menez Gwen, Lucky Strike, and Rainbow, along the MAR showed significant differences in tissue concentration of metals. Proportionality of metals in soft tissues of mussels reflected variation of water chemistry at different vents, which in turn conserved the order of trace metal prevalence in undiluted fluids. There were significant tissue-specific differences in trace metal compartmentalization for all metals investigated. Byssus thread contained the highest metal concentration among examined tissues, and thus it is suggested to be an important detoxification route. Size-dependent differences in metal concentrations were detected only for Hg, revealing a general trend of small mussels accumulating more metal than big mussels. Endosymbiont bacteria are shown to exclusively sequester Al from the host gill and contribute to removal of other toxic metals in mussels from Menez Gwen. The commensal parasite present in all mussels from Lucky Strike had higher tissue concentrations of Mn, Al, and Co than the host gill, unlike Cd and Hg which were considerably lower in the former, and thus its role in detoxification remains unclear. Bioaccumulation potential of vent bivalves and associated organisms are quantified as concentration factors and compared to make inferences on the putative role of the endosymbiont bacteria and the commensal parasite in detoxification of trace metals.

Animals↗

PubMed2005

Unique genetic compartmentalization of the SUF system in cryptophytes and characterization of a SufD mutant in Arabidopsis thaliana.

The mobilization of sulfur (SUF) system is one of three systems involved in iron-sulfur cluster biosynthesis and maintenance. In eukaryotes the SUF system is specific for the plastid and therefore of symbiotic origin. Analyses in cryptophytes showed a unique genetic compartmentalization of the SUF system, which evolved by at least two different gene transfer events. We analyzed one of the components, SufD, in the cryptophyte Guillardia theta and in Arabidopsis thaliana. We demonstrated that SufD fulfils house keeping functions during embryogenesis and in adult plants in A. thaliana.

Algal Proteins↗

PubMed2004

Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles.

The molecular regulation of the recruitment of initial signaling complexes at the TNF-R1 is poorly defined. We demonstrate here that within minutes internalized TNF-R1 (TNF receptosomes) recruits TRADD, FADD, and caspase-8 to establish the "death-inducing signaling complex" (DISC). In addition, we identified the TNF-R1 internalization domain (TRID) required for receptor endocytosis and provide evidence that TNF-R1 internalization, DISC formation, and apoptosis are inseparable events. Analyzing cell lines expressing an internalization-deficient receptor (TNF-R1 DeltaTRID) revealed that recruitment of RIP-1 and TRAF-2 to TNF-R1 occurred at the level of the plasma membrane. In contrast, aggregation of TRADD, FADD, and caspase-8 to establish the TNF-R1-associated DISC is critically dependent on receptor endocytosis. Furthermore, fusion of TNF receptosomes with trans-Golgi vesicles results in activation of acid sphingomyelinase and cathepsin D. Thus, TNF receptosomes establish the different TNF signaling pathways by compartmentalization of plasma membrane-derived endocytic vesicles harboring the TNF-R1-associated DISC.

Adaptor Proteins, Signal Transducing↗

PubMed2005

The use of the 4 + 5 extensor compartmental vascularized bone graft for the treatment of Kienböck's disease.

PURPOSE: The use of vascularized bone grafts for the treatment of Kienböck's disease may prevent ongoing lunate collapse and provide relief of wrist symptomatology. This study examines our experience with the use of the 4 + 5 extensor compartmental artery (ECA) bone graft for the treatment of Kienböck's disease. METHODS: A retrospective review was performed of all patients having pedicled vascularized bone grafts for Kienböck's disease between 1991 and 2002. Only those patients who had reconstruction with a 4 + 5 ECA graft were included in the study. Presurgical and postsurgical measurements included range of motion, grip strength, and pain evaluation. Measurements of the radiolunate angle, radioscaphoid angle, Stahl's index, and carpal height ratio were taken from presurgical and final follow-up radiographs. Postsurgical magnetic resonance imaging scans were also examined to verify revascularization of the lunate. Statistical analysis was performed using Student's t test. A chi-square test was used to evaluate the effects of lunate revascularization on radiographic progression of disease. Twenty-six 4 + 5 ECA vascularized bone grafts were performed as treatment for Kienböck's disease. The average patient age was 32 years. At the time of surgery 12 patients were graded as stage II, 10 as IIIA, and 4 as IIIB. Mean follow-up time was 31 months. RESULTS: At a mean follow-up of 3 months, motion improved from 68% to 71% of the unaffected side, grip strength improved from 50% to 89% of the unaffected side, and 92% of patients had significant improvement in their pain. Satisfactory results were seen in 85% of patients based on the Lichtman outcome score. Seventy-seven percent of patients showed no further collapse on postsurgical radiographs. Sixty-five percent of patients had follow-up magnetic resonance imaging scans at a mean of 20 months after surgery. Seventy-one percent of patients showed evidence of revascularization with improvement in the T2 and/or T1 signal. CONCLUSIONS: The 4 + 5 ECA bone graft provides a reliable alternative for the treatment of Kienböck's disease and may aid in lunate revascularization.

Adolescent↗

PubMed2006

A computational analysis of the impact of the transient genetic imbalance on compartmentalized gene expression during sporulation in Bacillus subtilis.

Sporulation in Bacillus subtilis serves as paradigm for the development of two different cell types (mother cell and prespore) from a single cell. Differential gene expression is achieved by restricting the activation of the key transcription factor sigmaF to the smaller prespore. By use of a combination of mathematical and experimental techniques we have recently shown that the volume difference determines cell fate and that the accumulation of the phosphatase SpoIIE on the asymmetrically placed septum is sufficient for prespore-specific sigmaF activation. Since compartmentalized gene expression is still obtained when SpoIIE cannot accumulate on the septum a number of alternative mechanisms have been proposed. These mechanisms focus on the difference in gene content between mother cell and prespore immediately after septation. Here the computational model is employed to show that under physiological conditions the transient genetic imbalance is unlikely to affect the septation-dependent release of sigmaF. The duration of the transient genetic imbalance is too short for the degradation of SpoIIAB to have an impact on the release of sigmaF. Moreover, the existence of an elusive IIE inhibitor, which has been proposed to become depleted in the prespore because of the transient genetic imbalance, is shown to be inconsistent with available experimental data. We conclude that the volume difference between the two compartments is the main determinant of cell fate.

Bacillus subtilis↗

PubMed2005

Increasing the speed of relaxometry-based compartmental analysis experiments in STEAM spectroscopy.

In this work we present a method for improving the speed of spin-spin relaxation time (T2) measurements for compartmental analysis in stimulated echo localized magnetic resonance spectroscopy without reducing the sampling density. The technique uses a progressive repetition time (TR) to compensate for echo time (TE) dependent variations in saturation effects that would otherwise modulate the received signal at short TRs. The method was validated in T2 studies on 10 young healthy subjects in spectroscopic voxels localized along either the right or left Sylvian fissure (2 x 2 x 1.5 cm3, 10 ms mixing time (TM), 2048 data points, 819.2 ms acquisition time). The TR was automatically adjusted so that TR-TM-TE/2 was kept constant as the TE was incremented. Compared to long TR T2 experiments, the progressive TR technique consistently replicated the T2 relaxation times and reference signals of the tissue water compartment while reducing the data acquisition time by more than 50%. The percent error was on average less than 2% for estimates of T2 and S(0) for the tissue water, an indication that the progressive TR technique is a useful method for determining the tissue water signal for internal referencing.

Adolescent↗

PubMed2005

Functional compartmentation of glycogen phosphorylase with creatine kinase and Ca2+ ATPase in skeletal muscle.

This manuscript discusses aspects of functional compartmentation in the regulation of metabolism. The functional consequences of enzymes coupling between creatine kinase, glycogen phosphorylase and sarcoplasmic reticular Ca2+ ATPase is examined. It is proposed that the coupling of creatine kinase and glycogen phosphorylase classifies as a novel class of diazyme complex with an important regulatory role in the inhibition of glycogenolysis at rest. In addition it is suggested that creatine kinase, glycogen phosphorylase and the sarcoplasmic reticular Ca2+ ATPase may couple to form a three-enzyme complex. From a consideration of the structure and chemical catalysis of the putative three-enzyme complex, a novel net reaction for glycogenolysis in the vicinity of the sarcoplasmic reticulum is suggested (Phosphocreatine+Glycogen+H(+)Creatine+Glycogen(n)(-1)+Glucose-1-Phosphate). The three-enzyme complex may also have an important role in inhibiting glycogenolysis at rest as well as improving the efficiency of high-energy phosphate transfer.

Animals↗

PubMed2006

A compartmental model of iron regulation in the mouse.

A simple compartmental model is developed for investigating the mechanism of iron homeostasis. In contrast to previous mathematical models of iron metabolism, the liver is included as a key site of iron regulation. Compartments for free iron in blood, diferric transferrin (Tf) in blood, hepatocytes, red blood cells, and macrophages are included, and their roles in iron regulation are explored. The function of hepcidin in regulating iron absorption is modeled through an inverse relationship between hepatocyte transferrin receptor 2 (TfR2) levels and the rate of iron export processes mediated by ferroportin (Fpn). Simulations of anemia and erythropoiesis stimulation support the idea that the iron demands of the erythroid compartment can be communicated through diferric Tf. The iron-responsive element of Fpn is found to be important for stabilizing intracellular iron stores in response to changing iron demands and allowing proper iron regulation through diferric Tf. The contribution of iron dysregulation to the pathogenesis of iron overload disorders is also investigated. It is shown that the characteristics of HFE hemochromatosis can be reproduced by increasing the setpoint of iron absorption in the duodenum to a level where the system cannot downregulate iron absorption to meet the iron excretion rate.

Anemia↗

PubMed2004

Hyperforin depletes synaptic vesicles content and induces compartmental redistribution of nerve ending monoamines.

Hyperforin, a phloroglucinol derivative found in Hypericum perforatum (St. John's wort) extracts has antidepressant properties in depressed patients. Hyperforin has a unique pharmacological profile and it inhibits uptake of biogenic monoamines as well as amino acid transmitters. We have recently showed that the monoamines uptake inhibition exerted by hyperforin is related to its ability to dissipate the pH gradient across the synaptic vesicle membrane thereby interfering with vesicular monoamines storage. In the present study we demonstrate that hyperforin induces dose-dependent efflux of preloaded [3H]5HT and [3H]DA from rat brain slices. Moreover, we show that hyperforin attenuates depolarization- dependent release of monoamines, while increasing monoamine release by amphetamine or fenfluramine. It is also demonstrated that preincubation of brain slices with reserpine is associated with dose- dependent blunting of efflux due to hyperforin. Our data indicate that hyperforin-induced efflux of [3H]5HT and [3H]DA reflect elevated cytoplasmic concentrations of the two monoamines secondary to the depletion of the synaptic vesicle content and the compartmental redistribution of nerve ending monoamines.

Analysis of Variance↗

PubMed2006

Conceptual, methodological and computational issues concerning the compartmental modeling of a complex biological system: Postprandial inter-organ metabolism of dietary nitrogen in humans.

A multi-compartmental model has been developed to describe dietary nitrogen (N) postprandial distribution and metabolism in humans. This paper details the entire process of model development, including the successive steps of its construction, parameter estimation and validation. The model was built using experimental data on dietary N kinetics in certain accessible pools of the intestine, blood and urine in healthy adults fed a [15N]-labeled protein meal. A 13-compartment, 21-parameter model was selected from candidate models of increasing order as being the minimum structure able to properly fit experimental data for all sampled compartments. Problems of theoretical identifiability and numerical identification of the model both constituted mathematical challenges that were difficult to solve because of the large number of unknown parameters and the few experimental data available. For this reason, new robust and reliable methods were applied, which enabled (i) a check that all model parameters could theoretically uniquely be determined and (ii) an estimation of their numerical values with satisfactory precision from the experimental data. Finally, model validation was completed by first verifying its a posteriori identifiability and then carrying out external validation.

Adult↗

PubMed2026

Membrane-associated compartmentalization of zearalenone biosynthetic enzymes and Syn2-associated zearalenone homeostasis in Fusarium graminearum.

Subcellular compartmentalization has attracted increasing attention in fungal secondary metabolism, particularly in the biosynthesis and trafficking of mycotoxins. However, the subcellular site of zearalenone (ZEA) biosynthesis and the mechanisms underlying its export in Fusarium graminearum remain poorly understood. ZEA is a polyketide mycotoxin that poses a serious threat to food safety through contamination of cereal grains and induces severe estrogenic effects in mammals. Its biosynthesis is governed by a dedicated biosynthetic gene cluster consisting of PKS4, PKS13, ZEB1, and ZEB2. In this study, we investigated the subcellular organization of the ZEA biosynthetic machinery and found that key biosynthetic enzymes accumulated in punctate structures that overlapped with small CMAC-positive vacuolar structures and were closely associated with FM4-64-labeled membranes. Furthermore, our results suggest that the syntaxin-like t-SNARE protein Syn2 contributes to extracellular ZEA accumulation and intracellular toxin homeostasis. Disruption of SYN2 abolished visible ZEA crystal formation on the hyphal surface and was associated with increased intracellular ZEA retention. This intracellular accumulation was accompanied by strong induction of the ZEA biosynthetic gene cluster and reduced cellular viability. Moreover, deletion of ZEB2 in the Δsyn2 background abolished ZEA production and restored cell viability, supporting an association between Zeb2-dependent ZEA biosynthesis and the cytotoxic phenotype of the Δsyn2 mutant. Together, our findings suggest a potential link between membrane-associated organization of ZEA biosynthetic enzymes, Syn2-associated ZEA distribution, intracellular toxin homeostasis, and fungal viability. Further studies will be required to define the precise mechanisms underlying ZEA transport and compartment function.

Fusarium graminearum↗

PubMedDate not supplied

Intercellular metabolic compartmentation in the brain: past, present and future.

The first indication of 'metabolic compartmentation' in brain was the demonstration that glutamine after intracisternal [14C]glutamate administration is formed from a compartment of the glutamate pool that comprises at most one-fifth of the total glutamate content in the brain. This pool, which was designated 'the small compartment,' is now known to be made up predominantly or exclusively of astrocytes, which accumulate glutamate avidly and express glutamine synthetase activity, whereas this enzyme is absent from neurons, which eventually were established to constitute 'the large compartment.' During the following decades, the metabolic compartment concept was refined, aided by emerging studies of energy metabolism and glutamate uptake in cellularly homogenous preparations and by the histochemical observations that the two key enzymes glutamine synthetase and pyruvate carboxylase are active in astrocytes but absent in neurons. It is, however, only during the last few years that nuclear magnetic resonance (NMR) spectroscopy, assisted by previously obtained knowledge of metabolic pathways, has allowed accurate determination in the human brain in situ of actual metabolic fluxes through the neuronal tricarboxylic acid (TCA) cycle, the glial, presumably mainly astrocytic, TCA cycle, pyruvate carboxylation, and the 'glutamate-glutamine cycle,' connecting neuronal and astrocytic metabolism. Astrocytes account for 20% of oxidative metabolism of glucose in the human brain cortex and accumulate the bulk of neuronally released transmitter glutamate, part of which is rapidly converted to glutamine and returned to neurons in the glutamate-glutamine cycle. However, one-third of released transmitter glutamate is replaced by de novo synthesis of glutamate from glucose in astrocytes, suggesting that at steady state a corresponding amount of glutamate is oxidatively degraded. Net degradation of glutamate may not always equal its net production from glucose and enhanced glutamatergic activity, occurring during different types of cerebral stimulation, including the establishment of memory, may be associated with increased de novo synthesis of glutamate. This process may contribute to a larger increase in glucose utilization rate than in rate of oxygen consumption during brain activation. The energy yield in astrocytes from glutamate formation is strongly dependent upon the fate of the generated glutamate.

Animals↗

PubMed2006

Long-term kainic acid exposure reveals compartmentation of glutamate and glutamine metabolism in cultured cerebellar neurons.

Glutamate neurotoxicity is implicated in most neurodegenerative diseases, and in the present study the long-term effects of the glutamate agonist kainic acid (KA) on cerebellar neurons are investigated. Primary cell cultures, mainly consisting of glutamatergic granule neurons, were cultured in medium containing 0.05 or 0.50mM KA for 7 days and subsequently incubated in medium containing [U-13C]glutamate or [U-13C]glutamine. The amount of protein and number of cells were greatly reduced in cultures exposed to 0.50 mM KA compared to those exposed to 0.05 mM KA. Glutamine consumption was not affected by KA concentration, whereas that of glutamate was decreased by high KA, confirming reduction in glutamate transport reported earlier. Neurons cultured with 0.50 mM KA and incubated with glutamate contained decreased amounts of glutamate, aspartate and GABA compared to those cultured with 0.05 mM KA. Incubation of cells exposed to 0.50 mM KA with glutamine led to an increased amount of glutamate compared to cells exposed to 0.05 mM KA, whereas the intracellular amounts of aspartate and GABA remained unaffected by KA concentration. Furthermore, mitochondrial metabolism of alpha-[U-13C]ketoglutarate derived from [U-13C]glutamate and [U-13C]glutamine was significantly reduced by 0.50 mM KA. The results presented illustrate differential vulnerability to KA and can only be understood in terms of inter- and intracellular compartmentation.

Animals↗

PubMed2006

Kinase suppressor of Ras1 compartmentalizes hippocampal signal transduction and subserves synaptic plasticity and memory formation.

The ERK/MAP kinase cascade is important for long-term memory formation and synaptic plasticity, with a myriad of upstream signals converging upon ERK activation. Despite this convergence of signaling, neurons routinely activate appropriate biological responses to different stimuli. Scaffolding proteins represent a mechanism to achieve compartmentalization of signaling and the appropriate targeting of ERK-dependent processes. We report that kinase suppressor of Ras (KSR1) functions biochemically in the hippocampus to scaffold the components of the ERK cascade, specifically regulating the cascade when a membrane fraction of ERK is activated via a PKC-dependent pathway but not via a cAMP/PKA-dependent pathway. Specificity of KSR1-dependent signaling also extends to specific downstream targets of ERK. Behaviorally and physiologically, we found that the absence of KSR1 leads to deficits in associative learning and theta burst stimulation-induced LTP. Our report provides novel insight into the endogenous scaffolding role of KSR1 in controlling kinase activation within the nervous system.

Adrenergic beta-Agonists↗