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PubMed1975

Cellular compartmentation of brain metabolism and its functional significance.

This paper reviews work from our laboratory on the metabolism and interrelations of isolated neuronal and neuropil fractions. The cell preparations are evaluated according to criteria of yield, purity, and integrity. Differences in the levels of activity of six groups of enzymes, of glucose metabolism, amino-acid metabolism, transmitter metabolism, acid hydrolysis, alkaline hydrolysis, and carbonic anhydrase have been followed, and neuronal and glial marker enzymes are proposed. Lysosomes and their enzymes are concentrated in neuronal perikarya. Metabolically, although no major differences in glucose oxidation have been found, there is considerable evidence of compartmentation of amino acids and their metabolism. At short times after injection of 3H-lysine as precursor in vivo, neuronal incorporation is high as compared with neuropil; at longer times the ratio is reversed, and we interpret this as evidence for the presence of a rapidly labeling protein fraction present in the neuromal perikarya but subsequently transported out. Neuronal protein incorporation is suppressed in the visual but not the motor cortex of dark-reared rats and is switched on following exposure to light; there is evidence that the suppressed fraction of neuronal protein synthesis includes the rapidly labeling component. A model for neuronal-glial metabolic interaction and its state-dependence in response to changes in the organism's environment and behavior is sketched out.

Amino Acids↗
PubMed1975

A hybrid compartmental model for the alligator Purkinje cell. I: Preferred somatopetal conduction of dendritic spikes and soma-axon interaction.

A compartmental hardware model of an alligator Purkinje cell is described, consisting of a branched dendritic tree with four zones of spike generation and electrically excitable soma and initial-segment regions. Passive properties of the model compartments are represented by a cable analog circuit. Simulated action potentials, generated by a combination of depolarizing and hyperpolarizing conductance changes, are triggered in active compartments when the simulated membrane potential passes through preset thresholds. These were set at values corresponding to 28mV depolarization in the dendrites, 22 mV in the soma, and 7 mV in the initial-segment compartment. Synaptic inputs consisting of brief (0.35 msec) rectangular conductance changes give rise to exponentially decaying postsynaptic potentials in the input compartment which are electrotonically spread to other compartments. Orthodromic activation of the model neuron by computer-generated random pulse trains generates a simple spike discharge in the initial-segment compartment without evoking complex spikes. Synchronized excitatory input to the same compartments, however, does evoke a complex spike response in the soma and initial segment, coupled with dendritic spikes. Following antidromic activation of the model neuron, dendritic spikes are not generated, demonstrating a tendency in the dendritic tree for preferential conduction of spikes toward the soma. Investigation of some of the factors underlying this tendency suggests that variations in voltage attenuation due to dendritic geometry, convergence of electrotonically spread dendritic spikes, and the relative durations of dendritic and somatic action potentials may contribute to it. The presence of a threshold gradient in the dendritic tree, proposed by Llinás and his coworkers, was not found to be necessary to explain this tendency toward somatopetal conduction, although it cannot be excluded by the model. Examination of the role of the conically shaped initial-segment region suggests that this zone may provide a low-pass filter for signals conducted electrotonically from the axon to the soma, blocking repolarization of the soma during the complex spike burst generated in the axon.

Action Potentials↗
PubMed1987

Noradrenergic sympathetic innervation of the spleen: V. Acute drug-induced depletion of lymphocytes in the target fields of innervation results in redistribution of noradrenergic fibers but maintenance of compartmentation.

Sympathetic noradrenergic fibers follow the vasculature into the white pulp of the spleen and branch from the periarteriolar plexuses into T lymphocyte zones. These lymphocytes, reported to express adrenergic receptors, are contacted directly by norepinephrine (NE) terminals and are putative targets of the locally released NE. Although this splenic innervation has been studied extensively, the functional interdependence of the lymphocytes and the sympathetic innervation is not well understood. To assess the effect of acute lymphocyte loss on the splenic innervation, T and B lymphocytes were depleted through treatment with cyclophosphamide (CY) or hydrocortisone acetate (HC). Despite reductions in spleen weight and cellularity, the total NE content (pmol) per spleen did not change. However, the NE concentration increased in the treated spleens. Although the general compartmental organization of the noradrenergic fibers in the treated spleens was similar to that of controls, the NE fibers redistributed and increased in density around the smaller central arteries in lymphocyte depleted spleens. The accommodation of these NE fibers to the changing environment of the white pulp suggests that the innervation to the spleen remains chemically stable despite a large disruption to the normal splenic milieu, but is capable of plasticity in the face of a shrinking white pulp.

Animals↗
PubMed1988

Compartmentation of enzymes interconverting aclacinomycins in Streptomyces species AM 33352.

The enzymatic interconversion of the aclacinomycins A (I), Y (II), and B (III) by Streptomyces spec. AM 33352/S 182 producing these aklavinone glycosides was investigated. The enzymes converting I to II and III, as well as vice versa, are located within different compartments separated by the cytoplasmic membrane. Aclacinomycin A (I) is biotransformed to II and III by the cell-free mycelium extract while the entire mycelium carries out the same type of conversion towards the opposite direction. Changes of enzyme activity are correlated to alterations in the ratio of aklavinone glycosides throughout the fermentation. A hypothesis is developed concerning the role of compartmentized oxidoreductase(s) in the passive flux of I from inside the cells to outside.

Aclarubicin↗
PubMed1989

On the transformation of compartmental systems and the indeterminacy of the volume of distribution.

A general compartmental system with multiple-point elimination is transformable to a single-point elimination system. Transformation is achieved by a similarity transformation of the rate constant matrix, A, with a diagonal matrix, D. The elements of D (1, d1, d2,...) are equivalent to the "first-pass" effect between compartments and compartment 1. Application of the derived transformation demonstrates that the volume of distribution as defined by the normalized first-moment function is a minimal volume of distribution when there is no "first-pass" effect between the drug input compartment and the observation compartment. In all other cases, the volume of distribution is a meaningless metric since it may be a minimal or maximal metric and the exact status is indeterminate. Theorems on the non-negativity of the elements of (-A)-1 are derived.

Chemistry, Pharmaceutical↗
PubMed1985

NMR compartmentalization of free water in the perfused rat heart.

Spin-lattice (T1) and spin-spin (T2) relaxation times have been measured on perfused rat hearts under two experimental conditions. T1 exhibits a monoexponential decay. On the other hand T2 has a decay with two components: a short one T2s and a long one T2l. These facts have been discussed according to cross-relaxation and a bicompartmentalization of tissue assuming a slow exchange model for spin-spin relaxation and a fast exchange model for spin-lattice relaxation. Increasing the osmotic pressure of the perfusion solution decreased the absolute density proton of the T2s compartment reflecting the loss of its water content. The paramagnetic ion manganese diminishes the values of T1 and those of the long component T2l without affecting its short component. Therefore the short component could be assigned to intracellular and the long component to extracellular free water. The extracellular T2 (459 ms) is approximatively 10-fold higher than the intracellular T2 (45 ms). With images of "pure T2" such a difference could be useful to enhance the contrast between organs and the surrounding liquid or between organs with different water compartmentalization.

Animals↗
PubMed1992

Multiexponential proton relaxation processes of compartmentalized water in gels.

The proton relaxation times, T1 and T2, of water in Sephadex gels, exhibiting pores of varying size (i.e., with exclusion limits of molecular weight between 10(3) and 10(5)) and water contents in the range 30 to 70% (w/w, weight of water to total weight), were measured at 20 MHz in the temperature range 5 to 50 degrees C. Multiexponential analysis of the relaxation curves revealed the existence of two relaxation components in all gel systems. A component with long T1 and T2 (T1,1 and T2,1) is associated with a large water fraction alpha 1,1 and alpha 2,1 and a component with short T1 and T2 (T1,2 and T2,2) with a small water fraction alpha 1,2 and alpha 2,2. An analysis of the temperature behavior of the relaxation components gives insight into the relaxation mechanisms. The relaxation process in water, compartmentalized in the gel matrix, is mainly controlled by dipole-dipole interactions. In addition, proton exchange processes between hydration water and hydroxyl groups of the matrix chain contribute under specific conditions and lead to a dramatic enhancement of the relaxation rate. In particular, for gels with small pores and with low water content proton exchange is observed. Compartments of water in gels could be models for compartments of water in biological tissues.

Dextrans↗
PubMed1994

Reperfused myocardial infarctions on T1- and susceptibility-enhanced MRI: evidence for loss of compartmentalization of contrast media.

The purpose of this study was to characterize the contrast caused by a susceptibility MRI contrast agents, on spin echo T2-weighted imaging of reperfused myocardial infarction. Our interest in this model focused on the expected requirement that such agents be compartmentalized in the tissue to cause signal loss on spin echo images, a condition which may not be present in reperfused infarcted myocardium. Accordingly, nine rats were subjected to 2 h of left coronary artery occlusion followed by 3 +/- 0.5 h of reperfusion prior to administration of contrast media. Three sets of MR images were acquired: (a) baseline axial images at the midventricle, both T1-weighted (TR/TE = 300/20) and T2-weighted (TR/TE = 1500/60); (b) T1-weighted images after administering a T1-enhancing agent, Gd-DTPA-BMA (0.2 mmol/kg), to document that contrast media is delivered to the reperfused infarction; and (c) T2-weighted images after administering the susceptibility agent, Dy-DTPA-BMA (1.0 mmol/kg). Gadolinium-enhanced T1 images depicted reperfused infarction as regions with greatly enhanced signal intensity compared with uninfarcted myocardium, indicating that contrast agent was delivered to the infarcted zone. Dysprosium-enhanced T2 images depicted the injury as a region of persistent signal intensity relative to depletion of signal in normal myocardium, consistent with failure of the contrast agent to cause signal loss. Similar infarction sizes were observed for unenhanced T2-weighted images (33 +/- 5%), gadolinium-enhanced T1-weighted images (36 +/- 5%) and postmortem staining (30 +/- 6%); strong correlations (r > 0.9) were noted in comparisons of these data.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Theory of heterogeneous relaxation in compartmentalized tissues.

A new model of compartmentalized relaxation--that which occurs for spins (protons) exchanging between compartments of different relaxation rates--is presented. This model generalizes previous ones by allowing spatially dependent relaxation within compartments. Solutions for the diffusion-Bloch equations are found via an efficient numerical technique known as the generalized moment expansion, and they agree well with the solutions to the standard two-site exchange equations (TSEE) for many typical situations. Specific models are developed for liposomes, red blood cells, capillaries, and arteries with respect to applied contrast agents. A parameter derived from tissue characteristics is introduced to predict the nature of the solutions. A new method is proposed for using contrast agents to detect capillaries, which exploits their high surface-to-volume ratio relative to the other elements of the vasculature.

Arteries↗
PubMed1997

MRI quantitative myocardial perfusion with compartmental analysis: a rest and stress study.

K1 (first-order transfer constant from arterial plasma to myocardium for Gd-DTPA) and Vd (distribution volume of Gd-DTPA in myocardium) were measured in vivo in a canine model (n = 5) using MRI-derived myocardial perfusion curves and a compartmental model. Perfusion curves were obtained after a bolus injection of Gd-DTPA (0.04 mM/kg) with an inversion-prepared fast gradient echo sequence. Myocardium and blood signal intensity were converted to a concentration of Gd-DTPA, according to a model appropriate for short (<1 s) interimage intervals characteristic of cardiac-triggered acquisitions. Before dipyridamole-induced stress, K1 and Vd, obtained from the fit of the MRI-derived perfusion curves, were 6.2 +/- 1.4 (mHz) and 17.5 +/- 4.2%, respectively. After dipyridamole infusion, a K1 increase of a factor of 2.82 +/- 0.72 was measured (P = 0.003). No change was observed in Vd (P = 0.98). These results suggest that the K1 increase after dipyridamole reflects a flow-related effect that can be useful to quantify the MRI-derived perfusion curves.

Animals↗
PubMed2004

Simultaneous 1H PFG-NMR and confocal microscopy of monolayer cell cultures: effects of apoptosis and necrosis on water diffusion and compartmentalization.

We induced apoptosis and necrosis in monolayer cultures of Chinese hamster ovary cells using okadaic acid and hydrogen peroxide (H2O2), respectively, and examined the effect on water diffusion and compartmentalization using pulsed-field-gradient (PFG) 1H-NMR and simultaneous confocal microscopy. In PFG experiments characterized by a fixed diffusion time (<4.7 ms) and variable b-values (0-27000 s/mm2), 1H-NMR data collected with untreated cells exhibited multiexponential behavior. Analysis with a slow-exchange model revealed two distinct cellular water compartments with different apparent diffusion coefficients (ADCs; 0.56, 0.06 x 10(-3) mm2/s) and volume fractions (0.96 and 0.04). During the first 12 hr of necrosis or apoptosis, the amount of water in the smallest compartment increased twofold before significant changes in cell density or plasma membrane integrity occurred. Over the same period, water content in the largest compartment decreased by a factor of >2 in apoptotic cells, in accordance with observed cell shrinkage, and changed little in necrotic counterparts, where only slight swelling was evident. These results indicate that PFG 1H-NMR serves as a sensitive indicator of early cell death in monolayer cultures, and can be used to distinguish apoptosis from necrosis. Measurements of restricted diffusion and water exchange are presented to elucidate the compartment origins and justify the model assumptions.

Animals↗
PubMed1994

Identification and characterization of striatal cell subtypes using in vivo intracellular recording and dye-labeling in rats: III. Morphological correlates and compartmental localization.

In the first two reports of this series, in vivo intracellular recording techniques were used to characterize the electrophysiological properties of two types of striatal neurons that had been identified by their distinct response patterns to stimulation of corticostriatal afferents. In this paper, we examined whether cells showing Type I or Type II response patterns also differed with respect to their morphology or compartmental localization by combining intracellular recording and Lucifer yellow staining with immunocytochemical localization of calbindin 28 kd immunoreactivity. In the majority of cases, both Type I and Type II neurons exhibited similar morphological characteristics, with 80% of the Type I cells (13/16) and all of the Type II cells (n = 40) being small or medium spiny neurons. In each case where the morphological class of the cell was different than the spiny cell class, the cell exhibited a Type I response pattern. These spiny neurons had somata that averaged 17.1 +/- 1.3 microns in diameter and gave rise to between four and eight primary dendrites. The axons typically arose from cell bodies (7/13 for Type I and 25/40 for Type II cells) and emitted extensive local axonal collaterals. However, the axons of Type I cells more frequently originated from the dorsal surface of the somata (9/13; 69%), whereas Type II axons more frequently arose from the ventral surface of the somata (25/35; 71%), which may account for their different extracellular waveforms. In coronally sectioned tissue (n = 18), the axons always projected laterally when the somata were located in the medial striatum and projected medially when the somata were in the lateral striatal region. In a subset of experiments (N = 22), Lucifer yellow-stained neurons were localized with respect to their position within the patch and matrix compartments of the striatum using subsequent staining for calbindin 28 kd immunoreactivity. Of the 20 labeled medium spiny neurons examined (Type II: N = 13; Type I: N = 7), 19 were located in the calbindin-positive matrix compartment. The only neuron localized to the patch compartment was a medium spiny cell that exhibited a Type II paired impulse response pattern. In addition, of the two aspiny neurons from this group with beaded dendrites, one was localized to the border between adjacent patch and matrix compartments, whereas the other was located completely within the matrix compartment. Therefore, despite their distinct paired impulse response patterns, the majority of both Type I and Type II neurons were medium spiny cells located in the matrix compartment of the striatum.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1997

Selenocompounds induce a redox modulation of protein kinase C in the cell, compartmentally independent from cytosolic glutathione: its role in inhibition of tumor promotion.

Since selenite and other redox-active selenocompounds can modify protein kinase C (PKC) in the test tube, we have determined whether or not this redox regulation occurs inside the cell despite having high concentrations of GSH and the role of this regulation in the inhibition of tumor promotion. By using phorbol ester-promoted JB6 epidermal cell transformation assay, the concentrations of selenite, selenocystine, and selenodiglutathione which are optimal for chemopreventive activity were determined. At such concentrations (0.5 to 2 microM) in the cells treated with these agents, only a slight but transient decrease in PKC activity was observed when measured with a low (5 microM), but not with a high (100 microM) concentration of ATP. However, when the cells were serum starved or pretreated with 2-deoxyglucose, there was a pronounced but transient inactivation of PKC when assayed with both low and high concentrations of ATP. The inactivation was reversed in the cell by an endogenous mechanism or by treatment with thiol agents in the test tube. In spite of a substantial (90%) depletion of GSH in the cells by pretreatment with buthionine sulfoximine, there was no further increase in the redox modification of PKC by selenite as well as no change in the inhibitory effect of selenite on the phorbol ester-stimulated induction of ornithine decarboxylase, which is an intermediate marker related to cell transformation. While GSH is known to influence certain actions of selenium, it may not be required to mediate the effects of selenite tested in this study. The water-soluble cytosolic GSH did not interfere with the redox modification of PKC probably due to the shielding of the cysteine-rich region of the enzyme by a weak hydrophobic association with the membrane. Due to the presence of cofactors in the crude cell extracts, PKC was more sensitive to selenite than in the purified form and was inactivated by low concentrations of selenite (IC50 = 0.05 microM). This modification was reversed by thiol agents as well as by NADPH. A protein disulfide reductase, which can regenerate PKC, was present in the homogenate. Conceivably, selenite and other selenocompounds induce a redox modification of cellular PKC, compartmentally independent from the cytosolic GSH, but intimately connected to a NADPH-dependent reductase system, to mediate, at least in part, some of the cancer-preventive actions.

Animals↗
PubMed1996

Compartmentalization of fucosyltransferase and alpha-L-fucosidase in human milk.

Several pathogenic agents of pediatric gastroenteritis are inhibited by fucosylated oligosaccharides of human milk. Biosynthesis and degradation of fucosyloligosaccharides is controlled by fucosyltransferase and alpha-L-fucosidase. The activity of these enzymes varies reciprocally over the course of lactation. We hypothesized that differences in the specific organization of these enzymes in compartments of human milk might contribute to such differences in activity. Therefore, the distribution of these enzymes in various compartments of human milk was investigated. After ultracentrifugation at 120,000g for 2h, the fucosyltransferase activity distributes evenly between the supernatant and the membranous pellet. Ultracentrifugation at 180,000g for 17 h further fractionated the milk into a clear supernatant, a fluff layer from the supernatant, and a pellet. The fluff was visualized by electron microscopy. The distribution of fucosyltransferase activity in colostrum was compared with that of mature milk from the same donor. In mature milk from Day 30 of lactation, most fucosyltransferase activity was in the membranous fluff fraction, while in colostrum from Day 5 of lactation, most of the fucosyltransferase activity was in the supernatant. In contrast to fucosyltransferase, fucosidase activity was found only in the soluble milk fraction; upon prolonged ultracentrifugation, most of this was membrane associated. The nature of human milk fucosidase was studied. This enzyme is glycosylated and exhibits several characteristics common to other fucosidases. Under the conditions found in human milk, it exhibits almost full activity. The variation in compartmentalization of fucosyltransferase activity during lactation may reflect variations in metabolism of the fucosyloligosaccharides of human milk that protect against disease.

Animals↗
PubMed1993

Compartmentalized expression of the alpha- and gamma-subunits of the acetylcholine receptor in recently fused myofibers.

The mRNAs encoding the subunits of the acetylcholine receptor are clustered at the level of the neuromuscular junction in adult muscle fibers. We have followed the distribution of the mRNAs encoding the alpha- and gamma-subunits during development of the diaphragm muscle in the mouse by whole-mount in situ hybridization. We show that the mRNAs encoding both subunits display a nonhomogeneous distribution as early as Day 13.5, when the first neuromuscular contacts are formed. Extrajunctional mRNAs disappear during the following days with a concomitant increase in contrast of the synaptic domains. gamma-subunit mRNAs become undetectable at the end of the first postnatal week, together with the appearance of epsilon-subunit mRNAs. Our results imply that the expression of the acetylcholine receptor genes, including the gamma-subunit gene, is compartmentalized soon after neuromuscular contacts have been established. This has important implications for the understanding of the molecular mechanisms of neuromuscular junction formation.

Animals↗
PubMed2000

Compartmentalization of the somite and myogenesis in chick embryos are influenced by wnt expression.

Muscles of the body and bones of the axial skeleton derive from specialized regions of somites. Somite development is influenced by adjacent structures. In particular, the dorsal neural tube and the overlying ectoderm have been shown to be necessary for the induction of myogenic precursor cells in the dermomyotome. Members of the Wnt family of signaling molecules, which are expressed in the dorsal neural tube and the ectoderm, are postulated to be responsible for this process. It is shown here that ectopically implanted Wnt-1-, -3a-, and -4-expressing cells alter the process of somite compartmentalization in vivo. An enlarged dorsal compartment results from the implantation of Wnt-expressing cells ventrally between the neural tube/notochord and epithelial somites, at the expense of the ventral compartment, the sclerotome. Thus, ectopic Wnt expression is able to override the influence of ventralizing signals arising from notochord and floor plate. This shift of the border between the two compartments was identified by an increase in the domain of Pax-3 expression and a complete loss of Pax-1 expression in somites close to the ectopic Wnt signal. The expanded expression of MyoD and desmin provides evidence that it is the myotome which increases as a result of Wnt signaling. Paraxis expression is also drastically amplified after implantation of Wnt-expressing cells indicating that Wnts are involved in the formation and maintenance of somite epithelium and suggesting that Paraxis is activated through Wnt signaling pathways. Taken together these results suggest that ectopic Wnts disturb the normal balance of signaling molecules within the somite, resulting in an enhanced recruitment of somitic cells into the myogenic lineage.

Animals↗
PubMed1999

Compartmentalization of interphase chromosomes observed in simulation and experiment.

Human interphase chromosomes were simulated as a flexible fiber with excluded volume interaction, which represents the chromatin fiber of each chromosome. For the higher-order structures, we assumed a folding into 120 kb loops and an arrangement of these loops into rosette-like subcompartments. Chromosomes consist of subcompartments connected by small fragments of chromatin. Number and size of subcompartments correspond with chromosome bands in early prophase. We observed essentially separated chromosome arms in both our model calculations and confocal laser scanning microscopy, and measured the same overlap in simulation and experiment. Overlap, number and size of chromosome 15 subcompartments of our model chromosomes agree with subchromosomal foci composed of either early or late replicating chromatin, which were observed at all stages of the cell cycle and possibly provide a functionally relevant unit of chromosome territory compartmentalization. Computed distances of chromosome specific markers both on Mb and 10-100 Mb scale agree with fluorescent in situ hybridization measurements under different preparation conditions.

Cell Cycle↗
PubMed1999

Selective degradation of unfolded proteins by the self-compartmentalizing HtrA protease, a periplasmic heat shock protein in Escherichia coli.

HtrA, which has a high molecular mass of about 500 kDa, is a periplasmic heat shock protein whose proteolytic activity is essential for the survival of Escherichia coli at high temperatures. To determine the structural organization of HtrA, we have used electron microscopy and chemical cross-linking analysis. The averaged image of HtrA with end-on orientation revealed a six-membered, ring-shaped structure with a central cavity, and its side-on view showed a two-layered structure. Thus, HtrA behaves as a dodecamer consisting of two stacks of hexameric ring. HtrA can degrade thermally unfolded citrate synthase and malate dehydrogenase but cannot when in their native form. HtrA degraded partially unfolded casein more rapidly upon increasing the incubation temperature. However, it hydrolyzed oxidized insulin B-chain, which is fully unfolded, at nearly the same rate at all of the temperatures tested. HtrA also rapidly degraded reduced insulin B-chain generated by treatment of insulin with dithiothreitol but not A-chain or intact insulin. Moreover, HtrA degraded fully unfolded alpha-lactalbumin, of which all four disulfide bonds were reduced, but not the native alpha-lactalbumin and its unfolded intermediates containing two or three disulfide bonds. These results indicate that unfolding of the protein substrates, such as by exposure to high temperatures or reduction of disulfide bonds, is essential for their access into the inner chamber of the double ring-shaped HtrA, where cleavage of peptide bonds may occur. Thus, HtrA with a self-compartmentalizing structure may play an important role in elimination of unfolded proteins in the periplasm of Escherichia coli.

Amino Acid Sequence↗