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PubMed1996

Multilayered dermal subcompartments for modeling chemical absorption.

Dermal penetration of chemicals and drugs is of concern to both toxicologists and pharmacologists. Environmental professionals try to limit exposure to chemicals using protective clothing and gloves or barrier creams to trap chemicals. Drug developers try to enhance penetration of chemicals through the skin for medical purposes. Both can use predictive biologically-based mathematical models to assist in understanding the processes involved. These models are especially useful when they are based on physiological and biochemical parameters which can be measured in the laboratory. Appropriately validated models based on conservation of mass, diffusion and chemical transport by flow can be predictive of human exposures. In this paper we develop two new physiologically-based pharmacokinetic (PBPK) skin models to predict blood concentrations of dibromomethane in rats after skin-only vapor exposures. These new models improve the predictions of the blood concentrations especially at the beginning of the exposures. Sensitivity analysis shows that the permeability constants followed by partition coefficients have the most impact on blood concentration predictions. With proper validation the new models could be used to improve species, dose, and duration extrapolations of chemical or drug penetration. They could also be used to investigate and predict concentrations of drugs or chemicals in the skin.

Animals↗
PubMed1985

Proteoglycan biosynthesis in chondrocytes: protein A-gold localization of proteoglycan protein core and chondroitin sulfate within Golgi subcompartments.

The intracellular pathway of cartilage proteoglycan biosynthesis was investigated in isolated chondrocytes using a protein A-gold electron microscopy immunolocalization procedure. Proteoglycans contain a protein core to which chondroitin sulfate and keratan sulfate chains and oligosaccharides are added in posttranslational processing. Specific antibodies have been used in this study to determine separately the distribution of the protein core and chondroitin sulfate components. In normal chondrocytes, proteoglycan protein core was readily localized only in smooth-membraned vesicles which co-labeled with ricin, indicating them to be galactose-rich medial/trans-Golgi cisternae, whereas there was only a low level of labeling in the rough endoplasmic reticulum. Chondroitin sulfate was also localized in medial/trans-Golgi cisternae of control chondrocytes but was not detected in other cellular compartments. In cells treated with monensin (up to 1.0 microM), which strongly inhibits proteoglycan secretion (Burditt, L.J., A. Ratcliffe, P. R. Fryer, and T. Hardingham, 1985, Biochim. Biophys. Acta., 844:247-255), there was greatly increased intracellular localization of proteoglycan protein core in both ricin-positive vesicles, and in ricin-negative vesicles (derived from cis-Golgi stacks) and in the distended rough endoplasmic reticulum. Chondroitin sulfate also increased in abundance after monensin treatment, but continued to be localized only in ricin-positive vesicles. The results suggested that the synthesis of chondroitin sulfate on proteoglycan only occurs in medial/trans-Golgi cisternae as a late event in proteoglycan biosynthesis. This also suggests that glycosaminoglycan synthesis on proteoglycans takes place in a compartment in common with events in the biosynthesis of both O-linked and N-linked oligosaccharides on other secretory glycoproteins.

Animals↗
PubMed1989

Precursors of chondroitin sulfate proteoglycan are segregated within a subcompartment of the chondrocyte endoplasmic reticulum.

Immunocytochemical methods were used at the levels of light and electron microscopy to examine the intracellular compartments of chondrocytes involved in extracellular matrix biosynthesis. The results of our studies provide morphological evidence for the compartmentalization of secretory proteins in the ER. Precursors of the large chondroitin sulfate proteoglycan (CSPG), the major proteoglycan species produced by chondrocytes, were present in the Golgi complex. In addition, CSPG precursors were localized in specialized regions of the ER. Link protein, a separate gene product which functions to stabilize extracellular aggregates of CSPG monomers with hyaluronic acid, was segregated similarly. In contrast, type II procollagen, another major secretory molecule produced by chondrocytes, was found homogeneously distributed throughout the ER. The CSPG precursor-containing ER compartment exhibits a variable tubulo-vesicular morphology but is invariably recognized as an electronlucent, smooth membrane-bounded region continuous with typical ribosome-studded elements of the rough ER. The observation that this ER structure does not stain with antibodies against resident ER proteins also suggests that the compartment is a specialized region distinct from the main part of the ER. These results support recent studies that consider the ER as a compartmentalized organelle and are discussed in light of the possible implications for proteoglycan biosynthesis and processing.

Animals↗
PubMed1993

The endoplasmic-sarcoplasmic reticulum of smooth muscle: immunocytochemistry of vas deferens fibers reveals specialized subcompartments differently equipped for the control of Ca2+ homeostasis.

Cryosection immunofluorescence and immunogold labeling with antibodies against specific markers were used in rat vas deferens smooth muscle fibers to reveal the molecular arrangement of the endomembrane system (referred to variously in the text as ER or sarcoplasmic reticulum [SR]; S-ER or ER/SR) known to participate in the control of Ca2+ homeostasis. The lumenal ER chaperon, immunoglobulin binding protein (BiP), as well as protein disulfide isomerase, and calreticulin, a Ca2+ binding protein expressed by most eukaryotic cells, appeared to be evenly distributed throughout the entire system (i.e., within [a] the nuclear envelope and the few rough-surfaced cisternae clustered near the nucleus; [b] single elements scattered around in the contractile cytoplasm; and [c] numerous, heterogeneous, mainly smooth-surfaced elements concentrated in the peripheral cytoplasm, part of which is in close apposition to the plasmalemma). All other structures, including nuclei, mitochondria, Golgi complex, and surface caveolae were unlabeled. An even distribution throughout the endomembrane system appeared also for the proteins recognized by anti-ER membrane antibodies. In contrast, calsequestrin (the protein that in striated muscles is believed to be the main actor of the rapidly exchanging Ca2+ storage within the lumen of the sarcoplasmic reticulum) was found preferentially clustered at discrete lumenal sites, most often within peripheral smooth-surfaced elements of moderate electron density. Within these elements dual labeling revealed intermixing of calsequestrin with the other lumenal ER proteins. Moreover, the calsequestrin-rich elements were enriched also in the receptor for inositol 1,4,5-trisphosphate, the second messenger that induces Ca2+ release from intracellular stores. These results document the previously hypothesized molecular heterogeneity of the smooth muscle endomembrane system, particularly in relation to the rapid storage and release of Ca2+.

Animals↗
PubMed2006

Interferon-induced, antiviral human MxA protein localizes to a distinct subcompartment of the smooth endoplasmic reticulum.

Human MxA protein belongs to the superfamily of dynamin-like large GTPases that are involved in intracellular membrane trafficking. MxA is induced by interferons-alpha/beta (IFN-alpha/beta) and is a key component of the antiviral response against RNA viruses. Here, we show that MxA localizes to membranes that are positive for specific markers of the smooth endoplasmic reticulum, such as Syntaxin17, but is excluded from other membrane compartments. Overexpression of MxA leads to a characteristic reorganization of the associated membranes. Interestingly, Hook3, mannose-6-phosphate receptor, and Lamp-1, which normally accumulate in cis- Golgi, endosomes, and lysosomes, respectively, also colocalized with MxA, indicating that these markers were redistributed to the MxA-positive compartment. Functional assays, however, did not show any effect of MxA on endocytosis or the secretory pathway. The present results demonstrate that MxA is an IFN-induced antiviral effector protein that resembles the constitutively expressed large GTPase family members in its capacity to localize to and reorganize intracellular membranes.

Animals↗
PubMed2003

A striking quality control subcompartment in Saccharomyces cerevisiae: the endoplasmic reticulum-associated compartment.

The folding of nascent secretory and membrane proteins is monitored by the endoplasmic reticulum (ER) quality control system. Misfolded proteins are retained in the ER and can be removed by ER-associated degradation. As a model for the ER quality control of multispanning membrane proteins in yeast, we have been studying mutant forms of Ste6p. Here, we identify mislocalized mutant forms of Ste6p that induce the formation of, and localize to, prominent structures that are absent in normal cells. We have named these structures ER-associated compartments (ERACs), based on their juxtaposition to and connection with the ER, as observed by fluorescence and electron microscopy. ERACs comprise a network of tubulo-vesicular structures that seem to represent proliferated ER membranes. Resident ER lumenal and membrane proteins are present in ERACs in addition to their normal ER localization, suggesting there is no barrier for their entry into ERACs. However, the forms of Ste6p in ERACs are excluded from the ER and do not enter the secretory pathway; instead, they are ultimately targeted for ER-associated degradation. The presence of ERACs does not adversely affect secretory protein traffic through the ER and does not lead to induction of the unfolded protein response. We propose that ERACs may be holding sites to which misfolded membrane proteins are specifically diverted so as not to interfere with normal cellular functions. We discuss the likelihood that related ER membrane proliferations that form in response to certain other mutant or unassembled membrane proteins may be substantially similar to ERACs.

ATP-Binding Cassette Transporters↗
PubMed1999

Glycosylphosphatidylinositol biosynthetic enzymes are localized to a stable tubular subcompartment of the endoplasmic reticulum in Leishmania mexicana.

Glycosylphosphatidylinositols (GPI) are essential components in the plasma membrane of the protozoan parasite Leishmania mexicana, both as membrane anchors for the major surface macromolecules and as the sole class of free glycolipids. We provide evidence that L.mexicana dolichol-phosphate-mannose synthase (DPMS), a key enzyme in GPI biosynthesis, is localized to a distinct tubular subdomain of the endoplasmic reticulum (ER), based on the localization of a green fluorescent protein (GFP)-DPMS chimera and subcellular fractionation experiments. This tubular membrane (termed the DPMS tubule) is also enriched in other enzymes involved in GPI biosynthesis, can be specifically stained with the fluorescent lipid, BODIPY-C5-ceramide, and appears to be connected to specific subpellicular microtubules that underlie the plasma membrane. Perturbation of microtubules and DPMS tubule structure in vivo results in the selective accumulation of GPI anchor precursors, but not free GPIs. The DPMS tubule is closely associated morphologically with the single Golgi apparatus in non-dividing and dividing cells, appears to exclude luminal ER resident proteins and is labeled, together with the Golgi apparatus, with another GFP chimera containing the heterologous human Golgi marker beta1,2-N-acetylglucosaminyltransferase-I. The possibility that the DPMS-tubule is a stable transitional ER is discussed.

Animals↗
PubMedDate not supplied

A preliminary study on the distribution of morphine and its glucuronides in the subcompartments of blood.

The distribution of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) in whole blood, plasma, and packed erythrocytes was studied. Parameters investigated were the hematocrit values (10, 42, 44, and 71%) and the water content of the samples. The blood-to-plasma ratio of morphine concentrations was unaffected by variations in hematocrit and water content, whereas the corresponding ratios for M3G and M6G were strongly influenced. Ratios were 0.53 to 0.65 and 0.52 to 0.62 in specimens with average hematocrit values (42 and 44%, respectively), and the ratios were 0.81 or 0.89 (hematocrit 10%) and 0.27 or 0.28 (hematocrit 71%) in blood samples with different hematocrit values. In contrast to the morphine conjugates, morphine was highly bound to or partitioned into red blood cells (beta e = 55.9). Although the present data are limited, they already demonstrate that conclusions drawn from pharmacokinetic studies and transferred to parent drug to metabolite ratios resulting from forensic blood samples may be biased by the particular biological matrix under investigation.

Centrifugation↗
PubMed2003

Equatorial segment protein defines a discrete acrosomal subcompartment persisting throughout acrosomal biogenesis.

The equatorial segment of the acrosome underlies the domain of the sperm that fuses with the egg membrane during fertilization. Equatorial segment protein (ESP), a novel 349-amino acid concanavalin-A-binding protein encoded by a two-exon gene (SP-ESP) located on chromosome 15 at q22, has been localized to the equatorial segment of ejaculated human sperm. Light microscopic immunofluorescent observations revealed that during acrosome biogenesis ESP first appears in the nascent acrosomal vesicle in early round spermatids and subsequently segregates to the periphery of the expanding acrosomal vesicle, thereby defining a peripheral equatorial segment compartment within flattened acrosomal vesicles and in the acrosomes of early and late cap phase, elongating, and mature spermatids. Electron microscopic examination revealed that ESP segregates to an electron-lucent subdomain of the condensing acrosomal matrix in Golgi phase round spermatids and persists in a similar electron-lucent subdomain within cap phase spermatids. Subsequently, ESP was localized to electron-dense regions of the equatorial segment and the expanded equatorial bulb in elongating spermatids and mature sperm. ESP is the earliest known protein to be recognized as a marker for the specification of the equatorial segment, and it allows this region to be traced through all phases of acrosomal biogenesis. Based on these observations, we propose a new model of acrosome biogenesis in which the equatorial segment is defined as a discrete domain within the acrosomal vesicle as early as the Golgi phase of acrosome biogenesis.

Acrosome↗
PubMed2005

Immunoisolaton of the yeast Golgi subcompartments and characterization of a novel membrane protein, Svp26, discovered in the Sed5-containing compartments.

The Golgi apparatus consists of a set of vesicular compartments which are distinguished by their marker proteins. These compartments are physically separated in the Saccharomyces cerevisiae cell. To characterize them extensively, we immunoisolated vesicles carrying either of the SNAREs Sed5 or Tlg2, the markers of the early and late Golgi compartments, respectively, and analyzed the membrane proteins. The composition of proteins was mostly consistent with the position of each compartment in the traffic. We found six uncharacterized but evolutionarily conserved proteins and named them Svp26 (Sed5 compartment vesicle protein of 26 kDa), Tvp38, Tvp23, Tvp18, Tvp15 (Tlg2 compartment vesicle proteins of 38, 23, 18, and 15 kDa), and Gvp36 (Golgi vesicle protein of 36 kDa). The localization of Svp26 in the early Golgi compartment was confirmed by microscopic and biochemical means. Immunoprecipitation indicated that Svp26 binds to itself and a Golgi mannosyltransferase, Ktr3. In the absence of Svp26, a considerable portion of Ktr3 was mislocalized in the endoplasmic reticulum. Our data suggest that Svp26 has a novel role in retention of a subset of membrane proteins in the early Golgi compartments.

Amino Acid Sequence↗
PubMed2006

Identification of a beta-dystroglycan immunoreactive subcompartment in photoreceptor terminals.

PURPOSE: Mutations in the dystrophin-associated glycoprotein complex (DGC) cause various forms of muscular dystrophy. These diseases are characterized by progressive loss of skeletal muscle tissue and by dysfunctions in the central nervous system (CNS). The CNS deficits include an altered electroretinogram, caused by an impaired synaptic transmission between photoreceptors and their postsynaptic target cells in the outer plexiform layer (OPL). The DGC is concentrated in the OPL but its exact distribution is controversial. Therefore, the precise distribution of beta-dystroglycan, the central component of the DGC, within the OPL of the mature chick retina, was determined. METHODS: Double immunolabeling with antibodies against beta-dystroglycan and against Bassoon, a component of the presynaptic cytomatrix, concentrated at the insertion point of the synaptic ribbon into the active zone of the photoreceptor synapses, showed a nonoverlapping distribution of both proteins within individual rod and cone photoreceptor terminals. The three-dimensional distribution of the DGC within the photoreceptor terminals was determined by reconstruction of the beta-dystroglycan immunoreactivity from serial electron microscopic sections. RESULTS: We found that beta-dystroglycan was not directly associated with the ribbon synapse but instead concentrated perisynaptically in processes extending from the photoreceptors into the OPL. The processes displayed dystroglycan immunoreactivity primarily along their lateral sides and at their tips. Processes from bipolar or horizontal cells were not labeled. CONCLUSIONS: The perisynaptic concentration of beta-dystroglycan in photoreceptor terminals suggests a novel domain within photoreceptor terminals with functions in synaptic transmission.

Animals↗
PubMed1979

Concentrations of immunoglobulin classes in subcompartments of the sheep lung.

The concentrations of IgA, IgG and IgM were measured in plasma, lung lymph and lung lavage fluid from adult sheep. Immunoglobulin concentrations in lymph and lavage fluid should fall sequentially during diffusive flux from the vascular compartment as a result of molecular sieving at the capillary endothelium and the alveolar epithelium. This was seen only for the IgG class. High concentrations of IgA and IgM in the interstitial (lymph) and luminal (lavage) compartments of the lung (relative to plasma levels) suggest either local synthesis of these classes or the existence of class specific active transport.

Animals↗
PubMed1995

Subcompartmental organization of the ventral (protrusor) compartment in the hypoglossal nucleus of the rat.

The extent and myotopic organization of the ventral (protrusor) compartment of the hypoglossal nucleus (nXII) in the rat is controversial. Of particular concern is the location of motoneurons that innervate the intrinsic (verticalis, transversus) as compared to extrinsic (genioglossus) tongue protrusor muscles. These issues were investigated with retrograde transport, lesion/degeneration/immunocytochemical, and classic Golgi staining techniques. Results from these experiments demonstrate the following: (1) the ventral compartment extends the entire rostrocaudal length of nXII and is organized into three longitudinally oriented subcompartments, one medial and one lateral within the boundaries of nXII, and one outside the confines of nXII, defined as the lateral accessory subcompartment; 2) the medial and lateral subcompartments contain motoneurons that innervate the intrinsic (verticalis, transversus) and extrinsic (genioglossus) tongue protrusor muscles, respectively, while the lateral accessory subcompartment innervates the geniohyoid muscle; (3) ventral subcompartments are unequal in size and vary along the rostrocaudal dimension of nXII. The medial subcompartment is largest caudally and smallest rostrally, while the converse is true for the lateral subcompartment. By contrast, the lateral accessory subcompartment is present only along the caudal one-half of nXII; (4) medial and lateral subcompartments are further organized into smaller subgroups. Medial and centromedial subgroups are discernible within the medial subcompartment, lateral and centrolateral subgroups within the lateral subcompartment. Both medial and lateral subgroups extend throughout the rostrocaudal length of nXII, whereas the centromedial and centrolateral subgroups are present only along the middle two-thirds of nXII where they form a central motoneuron band; (5) there is an inverse myotopic organization within the medial and lateral subcompartments such that proximal and distal portions of intrinsic and extrinsic protrusor muscles receive innervation from rostral and caudal motoneurons, respectively; and (6) there is a correlation between motoneuron morphology (size, shape and dendritic field domains), subcompartment localization, and myotopic specificity. Motoneurons in the medial subcompartment are small (mean = 23.08 microns), round to globular, with dendrites oriented medially, dorsomedially, dorsolaterally, and caudally, whereas lateral subcompartment motoneurons are large (mean = 29.49 microns), round to triangular, with dendrites directed mainly mediolaterally and dorsally. These data are relevant to understanding the functional organization of nXII and the motor control of the tongue. Results are further discussed relative to the convergence of multifunctional afferent systems in the ventromedial subcompartment of nXII.

Animals↗
PubMed1999

Compartmental organization of the olfactory bulb glomerulus.

Olfactory receptor cell (ORC) axons terminate in the olfactory bulb glomerular neuropil, where they synapse with dendrites of mitral, tufted, and periglomerular neurons. We investigated the organization of the glomerular neuropil by using antibodies to both single- and double-label constituents for analyses with confocal microscopy. Electron microscopy (EM) was employed to assess the distribution of synaptic appositions within the glomerulus. Adult Sprague-Dawley rats were processed for immunocytochemistry with olfactory marker protein (OMP), synaptophysin, synapsin 1, glial fibrillary acidic protein (GFAP), and/or microtubule-associated protein 2 (MAP2). Equivalent rats were processed for transmission EM. Double labeling for OMP and MAP2 revealed two distinctive subcompartments within glomeruli: an axonal compartment containing predominately primary afferent axons with individual dendritic inserts and a complementary dendritic compartment that excluded primary afferent axons. Areas not occupied by OMP or MAP2 immunoreactivity were either immunoreactive for GFAP, indicating a glial process, or were blood vessels. Synaptophysin and synapsin 1 also showed differential labeling within the glomerulus. Synaptophysin strongly colocalized with OMP, whereas synapsin 1 was associated most strongly with MAP2. Reconstructions of glomeruli from EM montages revealed interdigitating axonal and dendritic subcompartments. The axonal subcompartments were composed primarily of ORC processes with individual or small groups of dendrites interspersed. Dendritic subcompartments were composed predominately of dendritic processes. Primary afferent axodendritic and local-circuit dendrodendritic synapses segregated within the glomerulus into the axonal and dendritic subcompartments, respectively. The results support the hypothesis of subcompartmental organization within olfactory bulb glomeruli.

Animals↗
PubMed2002

[Correspondence analysis between occurrence type of Dendrolimus punctatus and topographical and vegetative features].

The relationship between the occurrence type of Dendrolimus punctatus and the geographical and vegetative features in subcompartments was analyzed using correspondence analysis and shown by a figure of cluster. The results showed that the majority subcompartments in which D. punctatus occurred frequently were at low elevation and low slope, and distributed among low hills or middle hills, while the subcompartments at high elevation or high slopes, or in low mountains or middle mountains were safe-type. The subcompartments with only one dominant species, especially Pinus elliottii, were easily attacked by D. punctatus. The subcompartments in conifer and broadleaf mixed forest had less insect pests than those in conifer mixed forest.

Altitude↗
PubMed1990

Time course of quantitative morphological changes of the autophagic-lysosomal compartment of murine seminal vesicle epithelial cells under the influence of vinblastine.

Changes of the autophagic-lysosomal compartment (ALC) of the murine seminal vesicle epithelial cells were monitored by electron microscopic morphometry during 36 h following a single 10 mg/kg bw dose of vinblastine sulfate (VBL), a widely used tool to cause an accumulation of the autophagic vacuoles (AVs). Three morphologically distinct subcompartments of the ALC, i.e. early autophagic vacuoles (AV1) being presumably prelysosomal autophagosomes, advanced AVs (AV2) containing material under degradation and dense bodies (DB) were defined. The ALC and its subcompartments expanded after VBL in a two-phase reaction. The first subcompartments to react significantly were AV1 and AV2 (at 30 min) followed by DBs with a 30 min delay. The ALC then ceased to grow until the 90th min when a second expansion phase started peaking around 8 h with a cytoplasmic volume fraction 15 times larger than in the untreated control. This second growth was entirely brought about by the expansion of the two AV subcompartments. After 8 h the volume fraction of both AV1 and AV2 decreased to cause a gradual regression of the ALC. AV1, however, already ceased to expand as early as after 6 h, i.e. during the last 2 h of the expansion phase of the ALC. Comparison of this time curve with the one we previously measured in mouse liver shows considerable differences between the two cell types. The growth curves of the AV subcompartments in our experiment along with others' kinetic data obtained in steady state cells not treated with VBL show that segregation (= formation of AV1) is possibly stimulated by VBL in our system.

Animals↗