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PubMed1987

Immunoelectron microscopic localization of fibronectin in the smooth muscle layer of mouse small intestine.

We studied the ultrastructural distribution of fibronectin in the smooth muscle layer of mouse small intestine with affinity-purified antibodies using the immunogold technique. Fibronectin was present over the pericellular area extending from the cell membrane to the extracellular matrix beyond the basal lamina. Distribution of the glycoprotein over the pericellular area was heterogeneous, i.e., it was localized more abundantly in the narrow space between smooth muscle cells, the gaps having a width of 60-80 nm where the two dense bands in adjacent cells matched each other. Such localization suggests that fibronectin contributes to cell adhesion. Within the basement membrane, gold label was localized both in lamina lucida and lamina densa, more densely in the latter than in the former. Fibronectin was also co-distributed with collagen fibers in the extracellular matrix. Within smooth muscle cells, gold particles were observed on rough endoplasmic reticulum and secretory vesicle-like structures. These results suggest that smooth muscle cells synthesize fibronectin and secrete it as a component of the basal lamina and extracellular matrix.

Animals↗

PubMed1992

Immunosuppression by human seminal plasma--extracellular organelles (prostasomes) modulate activity of phagocytic cells.

PROBLEM: Prostasomes are trilamellar to multilamellar vesicles produced by the acinar cells of the human prostate and are present in appreciable amounts in normal human semen. The aim of this work was to study the effect of prostasomes on human polymorphonuclear cell and monocyte function. METHODS: Functional activity of human neutrophils and monocytes was studied after incubation with prostasomes isolated from normal human seminal plasma. The following functional tests were employed: ability to ingest latex particles and opsonized bacteria (St. aureus) and ability to generate superoxide anion in response to PMA and FMLP. The latter was determined by measuring the superoxide-dismutase inhibitable reduction of ferricytochrome c to ferrocytochrome c at 550 nm. Expression of cell surface markers and interactions of prostasomes with cells were studied by cytofluorimetry. RESULTS: We show that prostasomes bind rapidly to the leukocyte cell membrane followed by internalization of adsorbed material. Interactions of prostasomes with neutrophils and monocytes inhibits their ability to phagocytose latex particles. The ability to ingest opsonized bacteria is, however, not impaired. Our results also show that incubation of leukocytes with prostasomes effectively inhibits superoxide anion generation in response to activation by PMA and FMLP. CONCLUSIONS: Prostasomes may play a complementary role to other immunosuppressive factors contained in the human semen. They may protect sperm cells from deleterious effects of phagocytosing cells, prolong their life, and consequently enhance the chance of conception. At the same time prostasomes may have a permissive effect on sexually transmitted diseases.

Cell Adhesion↗

PubMed1981

Effect of GABA-administration on murine neuroblastoma cells in culture. I. Increased membrane dynamics and formation of specialized contacts.

(Gamma aminobutyric acid) GABA was applied to cultures of mouse neuroblastoma cells of different ages at concentrations ranging from 10(-4) to 10(-6) M. The cultures were exposed to GABA either in short term experiments for 2 h to 2 days or for longer periods by adding the substance twice within 10 days at 5-day intervals. The following effects were observed: (1) There was a strong proliferation of coated vesicles, appearing to derive from the Golgi complex and the rough endoplasmic reticulum (RER), and also showing all intermediate stages of fusion and pinching off from the plasma membranes. (2) In numerous areas, electron-dense material aggregated at the inner aspect of the plasma membrane and around small invaginations of the plasmalemma. (3) The number and area of specialized contacts increased between cells and their processes. (4) Similar to cultures free of GABA, varicosities and terminal swellings of the cells and their processes were filled with small round vesicle, 40--60 nm in diameter, or with smooth, very large, empty-appearing vesicular inclusions, or with flat pleiomorphic vesicles. In addition, mitochondria and some formations of the smooth endoplasmic reticulum (SER) appeared, and primitive contacts (symmetrical densities) were formed. (5) Dense-cored vesicles were found peripherally and linearly arranged, surrounded by an electron-dense substance. (6) Electron-dense material of unknown origin was seen between cells or their processes near the peripherally arranged dense-cored vesicles. Exogenous GABA may play a specific role in the early stages of synaptogenesis, since it showed a positive effect on the neuroblastoma cells, which in the absence of GABA are only capable of forming primitive or immature presynaptic elements. The significance of the peripheral accumulation of dense-cored vesicles, accompanied by an amorphous, electron-dense substance occurring both intra- and extracellularly is discussed.

Animals↗

PubMed1986

Immunoultrastructural demonstration of prostatic acid phosphatase isoenzyme 2 in prostatic carcinoma.

Human prostatic acid phosphatase isoenzyme 2 (HPAcP-2) was isolated from semen. This purified enzyme was immunized to rabbit to produce polyclonal antibodies. The specificity of the antibodies was tested by Western blot transfer method. Rabbit IgG-peroxidase conjugate was prepared from the antiserum and used to localize HPAcP-2 in prostatic carcinoma. It was found that in the tumor glandular acinus the normal basal cells were replaced by tumor cells containing reaction product. In the tumor cells, the reaction product was seen in the cisternae of rough endoplasmic reticulum (ER) and Golgi apparatus. The secretory vesicles which contained reaction product-stained granules and some amorphous material were seen to fuse with the apical plasma membrane and discharged their content into the glandular lumen. On the other hand, some secretory vesicles in the tumor cells facing to the basement membrane also discharged their similar content into the extracellular spaces. Reaction product-stained granules were found in the interstitial spaces surrounding the tumor cells. These findings suggest that HPAcP-2 is synthesized on the bound ribosomes and discharged into the cisternae of rough ER. The molecules are transported to the Golgi cisternae. After concentration and packaging, HPAcP-2 molecules are then transferred to the secretory vesicles, and discharged into the glandular lumen and to the extracellular spaces. The isoenzyme released in the extracellular space may reach the blood stream through the interstitial spaces or the lymphatic system, resulting in the elevation of serum HPAcPase level in some prostatic cancer patients.

Acid Phosphatase↗

PubMed1987

Orientation of the brush-border membranal proteinase which specifically splits the catalytic subunit of cAMP-dependent protein kinase.

The active site of the rat intestinal brush-border membranal proteinase [Alhanaty E. and Shaltiel S. (1979) Biochem. Biophys. Res. Commun. 89, 323-332], which splits the catalytic subunit (C) of cAMP-dependent protein kinase with a remarkable specificity [Alhanaty E., Tauber-Finkelstein, M., Schmeeda, H. and Shaltiel, S. (1985) Curr. Topics Cell. Regul. 27, 267-277], is shown to face predominantly the cell exterior; vesicles prepared from these brush-borders (mostly sealed and right-side-out) fully express the proteinase activity as judged by the fact that there is no increase in activity upon rupture or solubilization of the vesicles. Although the brush-border vesicles contain a cAMP-dependent protein kinase, this membrane-bound kinase is not likely to be the physiological target of the proteinase, since it appears to have an intracellular orientation and, at least in the vesicles, to be inaccessible to the proteinase. It is, therefore, suggested that the physiological substrate of the proteinase might be either an extracellular cAMP-dependent protein kinase, which is lost (e.g. removed, inactivated or degraded) in the course of vesicle isolation, or a kinase domain in one of the family of proteins recently shown to have a considerable structural and conformational homology with C. Alternatively the physiological site of action of this kinase-splitting proteinase might be an intracellular organelle to which it is translocated by endocytosis.

Animals↗

PubMed1981

[Evidence of the recycling of vesicle membranes by means of morphometric measurement of the vesicle density (author's transl)].

Quantitative-electron microscopic investigations have been performed on large morphologically mixed synapses in the oculomotor nucleus of the trout with the aim to get some hints at recycling processes of vesicle membranes. For this reason vesicle density of the presynaptic area and number of vesicle attachment sites of the presynaptic membrane of the active zones within these mixed contacts have been estimated in two different experimental groups. Furthermore, vesicle density near the unmyelinated axolemma of the axon terminal has been measured in both groups. The results obtained support the view that a recycling of vesicle membranes occurs in morphologically mixed synapses, probably also over the axolemma of the so-called extended extracellular spaces, which are interrupting the contact area between the two neuronal elements. The question of a recycling of gap-junction-vesicles has not been answered.

Animals↗

PubMed2003

Lysosomal enzymes are released from cultured human macrophages, hydrolyze LDL in vitro, and are present extracellularly in human atherosclerotic lesions.

OBJECTIVE: Human atherosclerotic lesions have been shown to contain lipid droplets and vesicles resembling those of in vitro enzymatically modified LDL. However, little is known about the hydrolytic enzymes in the arterial intima that induce fusion of LDL particles and so produce lipid droplets or that induce foam cell formation. METHODS AND RESULTS: Human coronary atherosclerotic lesions obtained at surgery and at autopsy were stained for lysosomal acid lipase and cathepsin D. The extracellular areas of macrophage-rich intimal regions of the atherosclerotic lesions stained positively for both cathepsin D and lysosomal acid lipase, whereas normal arteries were negative. When monocyte-derived macrophages were incubated with opsonized zymosan to stimulate the release of lysosomal enzymes from the cells and LDL was incubated with the macrophage-conditioned media, the apolipoprotein B-100, cholesteryl esters, and triacylglycerols of LDL were hydrolyzed. These hydrolytic modifications rendered the LDL particles unstable and induced their fusion. Cultured macrophages and smooth muscle cells took up the hydrolase-modified LDL particles avidly and were transformed into foam cells. CONCLUSIONS: Our in vivo and in vitro results suggest that lysosomal enzymes released from macrophages may induce hydrolytic modification of LDL and foam cell formation in the human arterial intima.

Apolipoprotein B-100↗

PubMed1988

Ultrastructure of the anterior salivary gland cells of the giant leech, Haementeria ghilianii (Annelida, Hirudinea).

The giant anterior salivary gland cells from the large mammalian blood-sucking, glossiphoniid leech, Haementeria ghilianii, can be subdivided into three morphologically and functionally distinct regions: 1) a soma, responsible for the synthesis and storage of secretory products; 2) a long cell process, responsible for the storage and intracellular transport of the secretory vesicles; and 3) the site of exocytosis at the process terminal. The giant somata are densely packed with secretory vesicles. Deep plasmalemmal invaginations invade the soma and form an extensive system of extracellular lacunae. The rough endoplasmic reticulum (ER) and the Golgi apparatus are organized in the cell periphery, near the highly branched nucleus, and along the lacunae. The somata taper into long processes extending over several centimeters to the proboscis tip. These contain secretory vesicles through their whole length. In the process periphery, the vesicles are completely ensheathed by a concentric subplasmalemmal smooth ER cisterna. This originates deeply within the soma and extends through the whole cell process to its terminal. The ER provides support for up to several hundred longitudinally oriented microtubules. Secretion occurs at the very tip of the cell processes, each of which terminates at the proboscis tip at the base of a cuticular pore. We found synapses close to the sites of exocytosis, providing morphological evidence for neuronal control of secretion.

Animals↗

PubMed1976

Permeability of the amphibian pars intermedia to peroxidase injected intravascularly.

To study the penetration of protein from the blood into and through the pars intermedia of anurans, the electron-dense tracer, horseradish peroxidase (HRP), was injected into the vascular system of the frog, Rana pipiens. Pinocytotic vesicles were seen along plasma membranes of the stellate cells abutting the pericapillary spaces between the pars intermedia and pars nervosa. The HRP was seen within both the pericapillary spaces and these pinocytotic vesicles. In addition, the HRP was very prominent in the extracellular spaces between adjacent stellate and/or MSH cells and around nerve endings and thus, appeared to move from the vascular spaces and into the interior of the pars intermedia. Therefore, the poorly vascularized pars intermedia may have such a route for transfer of materials throughout the gland.

Animals↗

PubMed1979

Distribution and origin of acetylcholinesterase activity in the capillaries of the brain.

Areas containing AChE-positive capillaries were mapped in the brain of the cat and the guinea pig. Regions with AChE-positive capillaries mostly also contain neuronal elements with AChE activity. Electron-microscopical cytochemistry revealed localization of AChE in basement membranes of endothelial cells and pericytes very often in continuity with activity of the extracellular space. Intraendothelial AChE activity was seen only in pinocytic vesicles. The vascular AChE is thought to be of neuronal origin since no cytochemical evidence has been obtained for a synthesis of this enzyme in endothelial or other non-neuronal cells in the CNS.

Acetylcholinesterase↗

PubMed2003

Ca2+ signalling in brain synaptosomes activated by dinucleotides.

Diadenosine polyphosphates are a family of dinucleotides formed by two adenosines joined by a variable number of phosphates. Diadenosine tetraphosphate, Ap4A, diadenosine pentaphosphate Ap5A, and diadenosine hexaphosphate, Ap6A, are stored in synaptic vesicles and are released upon nerve terminal depolarization. At the extracellular level, diadenosine polyphosphates can stimulate presynaptic dinucleotide receptors. Responses to diadenosine polyphosphates have been described in isolated synaptic terminals (synaptosomes) from several brain areas in different animal species, including man. Dinucleotide receptors are ligand-operated ion channels that allow the influx of cations into the terminals. These cations reach a threshold for N- and P/Q-type voltage-dependent calcium channels, which become activated. The activation of the dinucleotide receptor together with the activation of these calcium channels triggers the release of neurotransmitters. The ability of Ap5A to promote glutamate, GABA or acetylcholine release has been recently described by the present authors in rat midbrain synaptosomes.

Animals↗

PubMed1986

Synaptogenesis in the retina of the cat.

We have studied the development of synapses in the retina of the cat from E(embryonic day)21 to adulthood. The inner plexiform layer (IPL) could be distinguished by E36, but at this age no synapses had formed, although compact processes had formed in the IPL and membrane specialisations had developed in adjacent processes. Conventional synapses form in the IPL from E45 and become increasingly numerous and differentiated over subsequent weeks. Extracellular space and cellular debris were prominent during the formation of these synapses. The conventional synapses appear to form principally between amacrine cells until E56, when ganglion cell dendrites could be identified as postsynaptic processes. Ribbon synapses characteristic of bipolar cells were identified around birth, suggesting that bipolar cells do not form synapses until that age. The outer plexiform layer (OPL) could be distinguished in central retina at E56. Extracellular space, debris of degenerating cells and mounds of agranular vesicles were prominent at this age but synapses were not observed until E59, when cone pedicles formed ribbon synapses onto horizontal cell processes. The first synapses clearly formed by spherules, also onto horizontal cells, were seen at E62. The central process of the postsynaptic triad, considered to be the dendrite of a bipolar cell, was first observed in both cone pedicles and rod spherules around birth, again suggesting that bipolar cells do not enter into synaptic arrangements until that age. Synaptogenesis in the OPL shows a strong centro-peripheral gradient; its initial stages were observed centrally in the late E50's but synapse formation was not complete in the retinal periphery until P(postnatal day)7 or later. We could not detect a centro-peripheral gradient in the formation of conventional synapses in the IPL, but the formation of ribbon synapses in this layer began centrally at birth and in the mid-periphery at P5. In summary, the first synapses to form in the retina are those which spread information laterally within the plexiform layers, between amacrine cells and from receptor to horizontal cells. The cells which carry information centrally, in particular bipolar cells, enter into synaptic arrangements considerably later. Further, retinal cells seem to form synapses in a distinct sequence: first amacrines, then receptors and lastly bipolar cells.

Animals↗

PubMed1986

Brief exposure to zinc is toxic to cortical neurons.

Recent evidence suggests that large amounts of releasable zinc are present in central synaptic vesicles, and that substantial (several hundred microM) transient elevations in extracellular zinc may accompany intense neuronal excitation. Brief pulse exposure of cortical cell cultures to similar concentrations of zinc resulted in widespread dose-dependent neuronal injury; exposure to higher concentrations resulted in the addition of glial injury. The results suggest that zinc should be included on the growing list of endogenous central neurotoxins which may be involved in the pathogenesis of CNS cell loss in a variety of disease states.

Animals↗

PubMed2004

Rapid vitamin D-dependent PKC signaling shares features with estrogen-dependent PKC signaling in cartilage and bone.

Our work is based on the hypothesis that steroid hormones regulate cells through traditional cytoplasmic and nuclear receptor-mediated mechanisms, as well as by rapid effects that are mediated by membrane-associated pathways. We have used the rat costochondral growth plate chondrocyte culture model to study the signaling mechanisms used by steroid hormones to elicit rapid responses and to modulate gene expression in target cells. Our studies show that the secosteroids 1,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] and 24,25-dihydroxyvitamin D3 [24R,25(OH)2D3], and the steroid hormone 17beta-estradiol, cause rapid increases in protein kinase C alpha (PKCalpha) activity, and many of the physiological responses of the cells to these regulators are PKC-dependent. Target cell specificity and the mechanisms by which PKCalpha is activated vary with each hormone. PKC activation initiates a signaling cascade that results in activation of the ERK1/2 family of mitogen activated protein kinases (MAPK), providing an alternate method for the steroids to modulate gene expression other than by traditional steroid hormone receptor-mediated pathways. In addition to their effects on growth plate chondrocytes, steroid hormones secreted by the cells also control events in the extracellular matrix through direct non-genomic regulation of matrix vesicles.

Animals↗

PubMed2006

Endocytic adaptors: recruiters, coordinators and regulators.

Clathrin-dependent endocytosis allows cells to bring plasma membrane and extracellular molecules into the cell. Forming a clathrin-coated vesicle requires the sequential action of numerous factors, beginning with endocytic adaptors. Adaptors are thought to initiate the process in two ways: by selecting cargo for packaging into the vesicle and assembling the clathrin coat and other components necessary to shape the vesicle. Here, we review recent work focusing on the sequential and cooperative interactions of adaptors with their binding partners, and how adaptors contribute to initial stages of endocytic internalization. The regulation of adaptors might be a key step for controlling endocytosis, and thus aid in homeostasis and cell physiology.

Animals↗

PubMed1995

Misrouting of tyrosinase with a truncated cytoplasmic tail as a result of the murine platinum (cp) mutation.

Mice homozygous for the platinum (cp) allele at the albino locus manifest severe oculocutaneous albinism despite the presence in vitro of tyrosinase activity at 25% wild-type levels. We demonstrate that the cp allele results from an A-->T substitution, changing a lysine residue at position 489 to a termination codon, with truncation of tyrosinase's cytoplasmic tail. In choroidal melanocytes of neonatal mutant mice, tyrosinase activity could be detected in the trans Golgi network, but was absent from melanosomes. Instead, it was detected in vesicles in the cell periphery and dendrites, and on the extracellular surface. In the retinal pigment epithelium, activity was present on the extracellular apical and basolateral surfaces. Our results demonstrate misrouting of a mutant tyrosinase lacking its cytoplasmic tail, providing an explanation for the severe effect of this mutation on ocular and cutaneous pigmentation.

Albinism, Oculocutaneous↗

PubMed2002

Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization.

Osteoblasts mineralize bone matrix by promoting hydroxyapatite crystal formation and growth in the interior of membrane-limited matrix vesicles (MVs) and by propagating the crystals onto the collagenous extracellular matrix. Two osteoblast proteins, tissue-nonspecific alkaline phosphatase (TNAP) and plasma cell membrane glycoprotein-1 (PC-1) are involved in this process. Mutations in the TNAP gene result in the inborn error of metabolism known as hypophosphatasia, characterized by poorly mineralized bones, spontaneous fractures, and elevated extracellular concentrations of inorganic pyrophosphate (PP(i)). PP(i) suppresses the formation and growth of hydroxyapatite crystals. PP(i) is produced by the nucleoside triphosphate pyrophosphohydrolase activity of a family of isozymes, with PC-1 being the only member present in MVs. Mice with spontaneous mutations in the PC-1 gene have hypermineralization abnormalities that include osteoarthritis and ossification of the posterior longitudinal ligament of the spine. Here, we show the respective correction of bone mineralization abnormalities in knockout mice null for both the TNAP (Akp2) and PC-1 (Enpp1) genes. Each allele of Akp2 and Enpp1 has a measurable influence on mineralization status in vivo. Ex vivo experiments using cultured double-knockout osteoblasts and their MVs demonstrate normalization of PP(i) content and mineral deposition. Our data provide evidence that TNAP and PC-1 are key regulators of the extracellular PP(i) concentrations required for controlled bone mineralization. Our results suggest that inhibiting PC-1 function may be a viable therapeutic strategy for hypophosphatasia. Conversely, interfering with TNAP activity may correct pathological hyperossification because of PP(i) insufficiency.

Alkaline Phosphatase↗

PubMed1991

Gingival biopsy in diagnosis of inborn storage diseases: a case of aspartylglycosaminuria.

The case described is that of a 9-yr-old girl presenting with aspartylglycosaminuria. Diagnosis of this lysosomal storage disease was guided by histologic study of gingival specimen sampled in the course of dental care. Transmitted electron microscopy (TEM) revealed many vesicles and cellular inclusions, altered collagenic formations, associated with abnormal extracellular matrix. Gingival biopsy is easily performed, is noniatrogenic, leaves nor scar, and could be properly used to help diagnose metabolic diseases in children.

Acetylglucosamine↗