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PubMed2006

Dopamine-induced graded intracellular Ca2+ elevation via the Na+Ca2+ exchanger operating in the Ca2+-entry mode in cockroach salivary ducts.

Stimulation with the neurotransmitter dopamine causes an amplitude-modulated increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)) in epithelial cells of the ducts of cockroach salivary glands. This is completely attributable to a Ca(2+) influx from the extracellular space. Additionally, dopamine induces a massive [Na(+)](i) elevation via the Na(+)K(+)2Cl(-) cotransporter (NKCC). We have reasoned that Ca(2+)-entry is mediated by the Na(+)Ca(2+) exchanger (NCE) operating in the Ca(2+)-entry mode. To test this hypothesis, [Ca(2+)](i) and [Na(+)](i) were measured by using the fluorescent dyes Fura-2, Fluo-3, and SBFI. Inhibition of Na(+)-entry from the extracellular space by removal of extracellular Na(+) or inhibition of the NKCC by 10 microM bumetanide did not influence resting [Ca(2+)](i) but completely abolished the dopamine-induced [Ca(2+)](i) elevation. Simultaneous recordings of [Ca(2+)](i) and [Na(+)](i) revealed that the dopamine-induced [Na(+)](i) elevation preceded the [Ca(2+)](i) elevation. During dopamine stimulation, the generation of an outward Na(+) concentration gradient by removal of extracellular Na(+) boosted the [Ca(2+)](i) elevation. Furthermore, prolonging the dopamine-induced [Na(+)](i) rise by blocking the Na(+)/K(+)-ATPase reduced the recovery from [Ca(2+)](i) elevation. These results indicate that dopamine induces a massive NKCC-mediated elevation in [Na(+)](i), which reverses the NCE activity into the reverse mode causing a graded [Ca(2+)](i) elevation in the duct cells.

Animals↗
PubMed1986

The ultrastructure of the rat primary decidual zone.

The rat primary decidual zone (PDZ) is a transitory, avascular region of transformed fibroblasts surrounding the implanting embryo. Tracer studies have indicated that the PDZ is selectively permeable to macromolecules, permeability decreasing with increasing molecular weight of the tracer. To clarify the morphological basis of the permeability barrier, we have studied the ultrastructure of the PDZ with particular emphasis on the intercellular features and cellular junctions. The cells of the PDZ were large and tightly packed; their apposed membranes showed extensive interdigitations in some regions, but elsewhere they were relatively straight. Tight junctions, gap junctions, and desmosomelike junctions were observed between decidual cells. The tight junctions usually consisted of one or two points of membrane fusion, and they were oriented both parallel and perpendicular to the long axis of the PDZ. These junctions were frequently associated with gap junctions. Scattered pockets of dilated extracellular space between decidual cells contained collagen fibrils and an amorphous, dense material. These extracellular components were also sequestered by the decidual cells in deep invaginations of the cell surface that were continuous with the extracellular space. Decidual cells also exhibited flangelike processes that penetrated the basal laminae of the adjacent epithelium and capillary endothelium. Our present observations indicate that decidual cells are connected by tight junctions, and a previous study demonstrated that macromolecules up to 40 kDa readily cross the PDZ; hence, the tight junctions appear to be discontinuous. We suggest that the structures restricting the movement of large macromolecules (66 kDa and larger) across the PDZ from blood vessels to the embryo may include discontinuous tight junctions, membrane interdigitations, and amorphous intercellular material.

Animals↗
PubMedDate not supplied

Cerebral ischaemia in the rat: increased permeability of post-synaptic membranes to horseradish peroxidase in the early post-ischaemic period.

An earlier study of the rat hippocampal stratum radiatum after transient cerebral ischaemia has shown cell membrane breaks, mainly post-synaptically, occurring as early as 20 min after an ischaemic episode. In the present study HRP was injected into the lateral ventricle 10-15 min after ischaemia and allowed to diffuse until 60 min post-ischaemia. Ultrastructural examination in the control animals, showed that HRP was localized exclusively in the extracellular space. After 10 min of transient ischaemia, HRP was not confined to the extracellular space, but was also seen in about 10% of apical dendrites. Only a very few pre-synaptic terminals showed the presence of HRP. Thus, there is evidence of early post-ischaemic membrane damage occurring in vivo in the apical dendrites of the CA-1 pyramidal cells.

Animals↗
PubMed1997

The role of glutamate transporters in glutamate homeostasis in the brain.

Glutamate transporters in neurones and glia, four of which have been cloned from mammals, play a crucial role in controlling the extracellular glutamate concentration in the brain. In normal conditions, they remove glutamate from the extracellular space and thereby help to terminate glutamatergic synaptic transmission and to prevent the extracellular glutamate concentration from rising to neurotoxic values. Glutamate transport on these carriers is thought to be driven by the cotransport of Na+, the counter-transport of K+, and either the cotransport of H+ or the counter-transport of OH-. Activating the transporters also activates an anion conductance in their structure, the anion flux through which is not coupled to glutamate movement and varies widely for the different transporters. During hypoxia or ischaemia, glutamate transporters can run backwards, releasing glutamate into the extracellular space, triggering the death of neurones and thus causing mental and physical handicap. The rate of glutamate release by this process is slowed by the acid pH occurring in hypoxia/ischaemia, which may help protect the brain during transient, but not sustained, ischaemia.

ATP-Binding Cassette Transporters↗
PubMed1990

[Ultrastructural studies of parental (L7811) and in vitro cultured (L7811-85) murine leukemic cell lines].

L7811 was an ascitic form of lymphocytic leukemia induced by myleran in 615 mice. Under electron microscope, cytoplasmic and intracisternal type A virus-like particles were observed. L7811-85 was a cell line established in vitro from the parental in vivo L7811 line. Instead of type A particles, mature and immature type C murine virus-like particles could be observed budding from the plasma membrane to extracellular space. With the in vitro subpassage of L7811-85 cells, more intracellular and extracellular type C particles appeared with an increase in its tumorigenicity. When L7811-85 cells, were inoculated IP to normal 615 mice, ascites tumor developed. The type A virus particles appeared again budding into cisterna of endoplasmic reticulum but not to extracellular space. The mechanism of virus particle type transformation remains to be studied.

Animals↗
PubMed1978

Fine structure of the stratum intermedium, stellate reticulum, and outer enamel epithelium in the enamel organ of the kitten.

Stratum intermedium, stellate reticulum and outer enamel epithelium at the secretion stage in lower second molars of 1 week old kittens were studied with the electron microscope after perfusion fixation. All cell types had a well-developed Golgi apparatus, free ribosomes and little RER. In the stratum intermedium, cytoplasmic processes occasionally contained many vesicles of different types and were connected to neighbouring cells by gap junctions. The number of gap junctions in the stratum intermedium increased greatly with advanced secretion. The cells of the stellate reticulum had large sheet-like cell extensions and surrounded large extracellular spaces. Often, two cell extensions ran parallel to each other, with a narrow extracellular space between them. The narrow spaces were filled with a fluffy material. The outer enamel epithelium showed a smooth basal surface when close to a blood vessel. Facing a larger expanse of connective tissue, the basal surface became folded, the basal lamina formed extended loops into the connective tissue and showed areas of increased density, and cell processes extended through the lamina into the connective tissue. The blood vessels associated with the outer enamel epithelium had many pericytes and resembled post-capillary venules. Macrophages showing vacuoles, aggregations of small vesicles, and peripheral flaps of cytoplasm were present, mainly in the stellate reticulum. These observations are compared with the structure of the human enamel organ, as reported in the literature, and their possible functional significance is briefly discussed.

Ameloblasts↗
PubMed2006

[Observation of binding sites of exogenous calmodulin and its extracellular effect in suspension-cultured Arabidopsis cell].

Peptide signals play very important roles in the process of plant development, growth and defense to various stresses. Apoplast calmodulin, putative extracellular peptide signal, not only existed in extracellular space, but also had biological functions. So it is important to provide evidences for extracellular calmodulin binding sites and mechanism of signaling. In this paper, exogenous FITC-ACaM2 was observed only in the outside of cell using Laser scanning confocal microscope (Fig. 2), and (35)S-ACaM2 binding to suspension-cultured Arabidopsis cells at 25 degrees C was equal to that at 4 degrees C (Fig. 3), provided direct evidences that exogenous calmodulin was not endocytosed into cytoplasm. SDS-PAGE and radiography showed (35)S-ACaM2 intactly existed in extracellular space of suspension-cultured Arabidopsis cells (Fig. 4). Exogenous ACaM2 could specifically promote activity of GTPase(Fig. 5) and [Ca(2+)](cyt) (Fig. 6). These results indicated exogenous calmodulin could bind to the surface sites of the suspension-cultured Arabidopsis cells, and then the extracellular signal was transferred into cytoplasm signal by transmembrane signaling to regulate the biological functions.

Arabidopsis↗
PubMed2002

Chordin-like CR domains and the regulation of evolutionarily conserved extracellular signaling systems.

In fruit flies as well as in humans the Short gastrulation (Sog)/Chordin protein functions as an antagonist of the signaling of decapentaplegic (Dpp)/bone morphogenetic protein (BMP) in the extracellular space. Such antagonism inhibits Dpp/BMP signaling by blocking its binding to the receptor. Modulation of Dpp/BMP signaling is phylogenetically conserved and is a key step for the establishment of the dorso-ventral axis in vertebrates and invertebrates. Molecular studies have shown that the inhibitory activity of Chordin on BMP resides in specific cysteine-rich (CR) domains. Interestingly, Chordin-like CR domains are present in a growing number of extracellular proteins, several of which appear to be involved in BMP signaling regulation. We review here the conservation of the Chordin and Sog proteins, and in particular their functional domain, the CR domain. We discuss how the study of CR domains may provide a general mechanism for the regulation of growth factor signaling in the extracellular space.

Amino Acid Sequence↗
PubMed1992

Ion concentrations, fluxes and electrical properties of the embryonic chicken lens.

The membrane properties of embryonic chicken lenses were characterized using isotopic and electrical techniques. The lenses had a relatively high water content (80%) and large extracellular space (12.5%). Isotopic uptake measurements indicated that the lens cytoplasm contained 118 mM K+ and 26 mM Cl-. A value for intracellular Na+ of 14 mM was obtained using Na(+)-sensitive microelectrodes. A double-exponential model was used to fit the efflux of 86Rb+, 22Na+, 36Cl- and [3H]mannitol (an extracellular space marker) from the lens. When perfused with artificial aqueous humor (AAH) solution, embryonic lenses exhibited membrane potentials of between -20 and -40 mV. The more negative values were generally observed in lenses from older embryos. A ouabain-sensitive component, contributing -7 mV to the membrane potential, was also identified. The relatively depolarized membrane potentials suggested that the lens membranes were only weakly selective for K+ over Na+. To test this further, lenses were perfused with AAH containing varying concentrations of K+. The resulting changes in potential were interpreted in terms of the Goldman model. The best fit of the Goldman potential equation indicated that, in the presence of ouabain, the chicken lens membranes had a relative permeability to K+, Na+ and Cl- of 1.0, 0.36, 0.51 respectively. Replacing most or all of the Na+ in the AAH caused only a small change in the membrane potential rather than the large hyperpolarization towards the K+ equilibrium potential predicted by the Goldman model. Including the K+ ionophore valinomycin in the low Na(+)-AAH solutions caused a large increase in 86Rb+ efflux but did not result in additional hyperpolarization. This suggested that the insensitivity of the membrane potential to reduced extracellular Na+ was not due to voltage or pH inactivation of lens K+ channels.

Animals↗
PubMed1980

Ultrastructure of developing human ductus arteriosus.

Histological and ultrastructural studies were made of 25 specimens of human ductus arteriosus obtained from abortion of autopsy, and ranging in age from 15 weeks of gestation to 7 years. Samples of ductus with normal muscular type structure exhibited active intimal thickening as early as 15 weeks' gestational age when the internal elastic lamina was found to be focally discontinuous. At the same time, intimal smooth muscle cells were closely arranged, and often intimately connected to cells of the tunica media. Ultrastructurally, both smooth muscle cells and endothelial cells at 15 weeks' gestational age contained abundant glycogen deposits. From 18-32 weeks' gestational age, glycogen deposits gradually disappeared, collagen fibres began to appear in the extracellular space and the first signs of smooth collagen fibres began to appear in the extracellular space and the first signs of smooth muscle cell degeneration became apparent. After birth, intimal thickening and degeneration of smooth muscle cells was much more pronounced. The ultrastructure of intimal smooth muscle cells indicated that intimal thickening was caused by smooth muscle cell migration as opposed to rapid proliferation; and both intracellular and extracellular membrane-bound lipid-filled vacuoles were commonly seen in the more advanced stages of degeneration. Of the ductus specimens examined, three were rich in elastic fibres. Two of these three specimens were from a group of 10 abortion cases, and the third was from a 2 weeks old full term infant who had been exposed to maternal rubella. The 2 weeks old infant had a widely patent ductus arteriosus; whether the two fetal specimens with ductus elastosis would have eventually developed into clinical patent ductus arteriosus was not clear.

Ductus Arteriosus↗
PubMed1976

[Cerebral cortex in normal pressure hydrocephalus: an electron microscopy study (author's transl)].

A cortical biopsy was taken at the time when ventricular pressure was measured, or a ventriculo-atrial shunt placed, in 11 patients with Normal Pressure Hydrocephalus (N.P.H.), and was studied with the electron microscope. In 9 cases, a rather typical electron microscopic picture with marked increase of extracellular space in an otherwise normal cortical neuropil was observed. 2 patients did not exhibit this pattern and, coincendentally, did not benefit from the placing of the shunt. As a control, about 600 cortical biopsies that had been taken for other reasons were reviewed. In the group, there were only 3 cortices that had a pattern of increased extracellular space similar to the described in N.P.H. On review of the clinico-pathologic data of these cases, it was felt that all 3 probably represented cases of normal pressure hydrocephalus. It is concluded that the ultrastructure of the cerebral cortex is of at least nosological interest in the study of N.P.H.

Cerebral Cortex↗
PubMedDate not supplied

Diffusion constraints and neuron-glia interaction during aging.

Changes in brain extracellular space (ECS) volume, composition, and geometry are a consequence of neuronal activity, of glial K+, pH, and amino acid homeostasis, and of changes in glial cell morphology, proliferation, and function. They occur as a result of repetitive neuronal activity, seizures, anoxia, injury, inflammation, and many other pathological states in the CNS, and may significantly affect signal transmission in the CNS. Activity-related or CNS damage-related cellular swelling is compensated for by ECS volume shrinkage and, as a consequence, by a decrease in the apparent diffusion coefficients (ADCs) of neuroactive substances diffusing in the ECS. Changes in cellular morphology, such as occur during aging, could also result in changes of ECS volume and geometry. We provide evidence for limited diffusion in rat cortex, corpus callosum, and hippocampus in the aging brain that correlates with changes in glial volume and the extracellular matrix. In all structures, the mean ECS volume fraction alpha (alpha = ECS volume/total tissue volume) and nonspecific uptake k' are significantly lower in aged rats (26-32 months old) than in young adult brain. Compared to young adult brain, in the aged brain we found an increase in GFAP staining and hypertrophied astrocytes with thicker processes which, in the hippocampus, lost their radial organization. The tortuosity (lambda = square root of D/ADC) was lower in the cortex and CA3 region. Immunohistochemical staining for fibronectin and chondroitin sulfate proteoglycans revealed a substantial decrease that could account for a decrease in diffusion barriers. Diffusion parameters alpha, lambda, and k' in the aging brain after cardiac arrest changed substantially faster than in the young adult brain, although the final values were not significantly different. This suggests that the smaller extracellular space during aging results in a greater susceptibility of the aging brain to anoxia/ischemia, apparently due to a faster extracellular acidosis and accumulation of K+ and toxic substances, for example, glutamate. We conclude that during aging the movement of substances is more hindered in the narrower clefts. This is partly compensated for by a decrease in the diffusion barriers that may be formed by macromolecules of the extracellular matrix. Diffusion parameters can affect the efficacy of synaptic as well as extrasynaptic transmission by a greater accumulation of substances, because they diffuse away from a source more slowly, or induce damage to nerve cells if these substances reach toxic concentrations. Diffusion parameters are also of importance in the "crosstalk" between synapses, which has been hypothesized to be of importance during LTP and LTD. We can, therefore, assume that the observed changes in ECS diffusion parameters during aging can contribute to functional deficits and memory loss.

Aging↗
PubMed2004

Temporal bone histopathology in alport syndrome.

OBJECTIVE: To determine the histopathologic abnormalities within the cochlea in Alport syndrome. BACKGROUND: Alport syndrome, which manifests as hereditary nephritis and sensorineural hearing loss (SNHL), is caused by mutations in genes that code for the proportional, variant3, proportional, variant4, and proportional, variant5 chains of type IV collagen. The proportional, variant3, proportional, variant4, and proportional, variant5 chains of type IV collagen are present in the basement membrane of the organ of Corti. Previous temporal bone studies have failed to identify histopathologic correlates for the SNHL. METHODS: We examined temporal bones from nine individuals with a clinical diagnosis of Alport syndrome. One of our cases also had genetic testing that showed a mutation in the type IV collagen proportional, variant5 chain gene. RESULTS: By light microscopy, eight of nine cases demonstrated two unique pathologic changes: 1) a "zone of separation" between the basilar membrane and overlying cells of the organ of Corti and 2) presence of cells filling the tunnel of Corti and extracellular spaces of Nuel. The cytologic losses of hair cells, stria vascularis, and cochlear neuronal cells were insufficient to account for the observed SNHL in our cases. Electron microscopy was performed in four cases; all four demonstrated the following: 1) the zone of separation that was observed at light microscopy occurred between the basement membrane and the basilar membrane, 2) the cells within the tunnel of Corti and spaces of Nuel were morphologically similar to supporting cells, and 3) the basement membrane of strial capillaries and the spiral vessel (under the basilar membrane) were normal. CONCLUSIONS: The histopathologic correlates of cochlear involvement in Alport syndrome are abnormalities of the basement membrane of cells of the organ of Corti and dysmorphogenesis (cellular infilling of the tunnel and extracellular spaces) of the organ of Corti. We hypothesize that these abnormalities result in SNHL by altering cochlear micromechanics.

Adolescent↗
PubMed1975

Volume adjustment by renal medullary cells in hypo- and hyperosmolal solutions containing permeant and impermeant solutes.

1. The changes in the volumes of cells in slices (thickness 0-3-0-4 mm) of rat renal outer and inner medulla have been investigated during aerobic incubation for 20 min at 37 degrees C in Krebs phosphate-bicarbonate Ringer modified by the addition of urea or sucrose in order to produce a range of media hypo- and hyperosmolal with respect to the calculated tissue fluid osmolalities in these regions. 2. On the assumption that under these conditions the measured inulin space approximates to the true extracellular space (ECS), it was found that osmotic swelling or shrinkage of cells was not accompanied by any significant variation in the absolute size of the ECS. 3. Calculated cell volume changes in both regions were minimal when slices were incubated in urea-containing media iso-osmolal with tissue fluids in that region. In sucrose-containing media minimal cell volume changes occurred when media were hypo-osmolal in relation to tissue fluids by a factor of approximately 0-68. 4. In all except the most hypo-osmolal media studied, calculated cell volume changes (as percentage of initial volume) were linearly related to the reciprocal of the incubation media osmolalities. The points of interception of the regression lines on the cell volume axis were dependent upon both the region studied and the composition of the incubation medium (urea or sucrose). 5. These changes were accompanied by variations in slice solute concentrations. Slice [Na] was greatest, and slice [K] least, following incubation in those media producing the greatest percentage changes in cell volume. 6. The volume of distribution [14-C]sucrose within the inner medulla was 61-7 plus or minus 2-5 mul./100 mg wet weight of tissue (mean plus or minus S.E., n equals 6) after 10 min incubation. The increase to 70-8 plus or minus 4-2 mul./100 mg (n equals 6) after 100 min was not significant (0-1 greater than P greater than 0-05). The volume of distribution within the outer medulla rose markedly during this period, from 38-1 to 58-2 mul./100 mg.

Animals↗
PubMed2002

Nitric oxide in the penumbra of a focal cortical necrosis in rats.

After a focal cortical freezing lesion in rats, nitric oxide (NO) end products were studied with microdialysis in the extracellular space of the penumbra throughout the whole period of secondary expansion of the cortical necrosis (i.e. 24 h). Under baseline conditions, the dialysate concentration of nitrate (nitrite) was 1.8 +/- 0.78 microM (5.00 +/- 1.50 microM) in the sham-operated group and 2.28 +/- 0.62 microM (3.25 +/- 1.32 microM) in the trauma group. In animals of both groups, these parameters neither showed significant alterations within the observation period compared with baseline values nor between the groups at each individual study time point. After focal cortical trauma, NO does not mediate secondary necrosis expansion via the extracellular space.

Animals↗
PubMed2001

Axonal L-type Ca2+ channels and anoxic injury in rat CNS white matter.

We studied the magnitude and route(s) of Ca2+ flux from extra- to intracellular compartments during anoxia in adult rat optic nerve (RON), a central white matter tract, using Ca2+ sensitive microelectrodes to monitor extracellular [Ca2+] ([Ca2+]o). One hour of anoxia caused a rapid loss of the stimulus-evoked compound action potential (CAP), which partially recovered following re-oxygenation, indicating that irreversible injury had occurred. After an initial increase caused by extracellular space shrinkage, anoxia produced a sustained decrease of 0.42 mM (29%) in [Ca2+]o. We quantified the [Ca2+]o decrease as the area below baseline [Ca2+]o during anoxia and used this as a qualitative index of suspected Ca2+ influx. The degree of RON injury was predicted by the amount of Ca2+ leaving the extracellular space. Bepridil, 0 Na+ artificial cerebrospinal fluid or tetrodotoxin reduced suspected Ca2+ influx during anoxia implicating reversal of the Na+/Ca2+ exchanger as a route of Ca2+ influx. Diltiazem reduced suspected Ca2+ influx during anoxia, suggesting that Ca2+ influx via L-type Ca2+ channels is a route of toxic Ca2+ influx into axons during anoxia. Immunocytochemical staining was used to demonstrate and localize high-threshold Ca2+ channels. Only alpha1(C) and alpha1(D) subunits were detected, indicating that only L-type Ca2+ channels were present. Double labeling with anti-neurofilament antibodies or anti-glial fibrillary acidic protein antibodies localized L-type Ca2+ channels to axons and astrocytes.

Animals↗
PubMed1978

Effect of colchicine on estrogen action. I. Inhibition of 17 beta-estradiol-induced water and potassium uptake in the immature rat uterus.

The effects of colchicine on 17 beta-estradiol-induced water and electrolyte uptake in the uterus of the immature rat have been examined 6 h after treatment with this estrogen. Estradiol stimulates an increase in total uterine Na+, K+ and water while intracellular Na+ and K+ concentrations remain relatively unchanged. Assuming the sodium space is equivalent to the extracellular space, the extracellular fluid compartment increases about 84% in response to estradiol. Similarly, the intracellular compartment increases by about 62%. The uptake of water into the cellular compartment may be a direct response to a stimulation of K+ accumulation by uterine cells. Colchicine inhibits both estradiol-induced rise in intracellular potassium and both intra- and extracellular water.

Animals↗
PubMedDate not supplied

Optical imaging reveals reduced seizure spread and propagation velocities in aged rat brain in vitro.

Old age is the most common time for patients to develop epileptic seizures, and due to their frequent unusual clinical presentation the diagnosis of epilepsy is often delayed in the elderly. It is as yet unknown if pronounced alterations in the plastic properties of aging nervous tissue contribute to these phenomena. We employed a non-lesional in vitro epilepsy model to study seizure susceptibility, spread pattern, and propagation velocities in combined hippocampal-entorhinal cortex slices of aged rats and controls using electrophysiological methods and imaging of intrinsic optical signals. In aged animals we saw a less extensive spread of seizure-like events into areas adjacent to the region of onset of activity and a decreased spread velocity in various anatomical regions. In addition, both the activity-dependent shrinkage of the extracellular space (ECS)-volume and the extracellular K(+) concentration were significantly reduced compared to controls. The results of this study are consistent with the clinical observation that epileptic seizures in the elderly have a reduced tendency to spread. In addition, our data suggest that in the absence of structural lesions seizure susceptibility in the aging brain is not increased.

Aging↗