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PubMedDate not supplied

Compartmentalized NRG signaling and PDZ domain-containing proteins in synapse structure and function.

The synapse-specific synthesis of the acetylcholine receptor (AChR) is mediated by multiple mechanisms including compartmentalized signaling induced by neuregulin (NRG). This paper presents evidence that NRG receptors--ErbB receptor tyrosine kinases interact with distinct PDZ domain-containing proteins that are localized at the neuromuscular junction (NMJ). ErbB4 associates with the PSD-95 (also known as SAP90)-family members including PSD-95, SAP97, and SAP102 whereas ErbB2 interacts with Erbin and PICK1. Although, ErbB kinases are concentrated at the NMJ, they are not colocalized with the AChR in cultured muscle cells even in the presence of agrin. Co-expression of PSD-95 causes ErbB4 to form clusters in COS cells. We propose that PDZ domain-containing proteins play a role in anchoring ErbB proteins at the neuromuscular junction, and/or mediating downstream signaling pathways. Such mechanisms could be important for the maintenance and function of the synapse.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Effects of the ionophores valinomycin, ionomycin and gramicidin A on the element compartmentation in cultured rat hepatocytes.

The element compartmentation in cultured rat hepatocytes was studied by electron probe X-ray microanalysis of freeze-dried cryosections after exposure of the cells to the ionophores valinomycin, ionomycin or gramicidin A. The most striking effect of these ionophores is the decrease of the intracellular potassium/sodium ratio from values of approximately 10 under control conditions to values below 1 after application of the ionophores. Changes of sodium, potassium and chloride are similar in cytoplasm and nucleus. However, elemental changes are delayed or impeded in mitochondria with respect to the surrounding cytoplasm. The water portion of cytoplasm and mitochondria slightly increases. Besides that, each ionophore has specific effects on the intracellular ion distribution. As compared to gramicidin A and ionomycin, valinomycin does not change the intracellular chloride content. Ionomycin induces calcium accumulation in mitochondria. The cytotoxic effects of the studied ionophores on the intracellular element distribution are more complex than supposed from their ion selective properties in membranes.

Animals↗
PubMed2002

A platform for compartmentalized protein synthesis: protein translation and translocation in the ER.

Recent advances in the study of protein translocation across the membrane of the endoplasmic reticulum include insights into the mechanism of signal-sequence function. Biochemical and genetic studies have provided further evidence that lumenal proteins perform direct roles in secretory protein translocation and in the regulation of protein-conducting-channel permeability during membrane protein integration. A hypothesis identifying the endoplasmic reticulum as a site of mRNA localization and compartmentalized protein synthesis has been suggested.

Biological Transport, Active↗
PubMed1998

Membrane compartmentation is required for efficient T cell activation.

The plasma membrane of mammalian cells contains detergent-resistant membrane rafts enriched in glycosphingolipids and cholesterol. Although several important signaling molecules have been found in such rafts, evidence documenting a functional role for their localization has been scarce. Using a fractionation scheme that preserves tyrosine phosphorylation, we show that T cell activation leads to a striking compartmentation in the rafts of activated T cell receptor and associated signal-transducing molecules. Conditions that reversibly disrupt raft structure either by dispersing their contents or by forcing their internalization reversibly disrupt the earliest steps of T cell activation. Thus, raft integrity is a prerequisite for efficient T cell receptor signal transduction.

Animals↗
PubMed1992

Metabolic heterogeneity of carbon substrate utilization in mammalian heart: NMR determinations of mitochondrial versus cytosolic compartmentation.

Carbon-13 (13C) nuclear magnetic resonance (NMR) spectroscopy can be used to target specific pathways of intermediary metabolism within intact tissues and was employed in this study to evaluate the compartmentation of pyruvate metabolism between the cytosol and mitochondrial matrix. The distribution of 13C into the tissue alanine, lactate, and glutamate pools was evaluated during metabolism of [3-13C]-pyruvate in intact, isolated perfused rabbit hearts with and without activation of pyruvate dehydrogenase activity by dichloroacetate (5 mM). Equilibrium between the intracellular alanine and pyruvate pools was in evidence from the rapid evolution of the steady-state 13C signal arising from the 3-carbon of alanine in intact hearts perfused with 2.5 mM 99.4% [3-13C]pyruvate. Augmented pyruvate oxidation, in response to perfusion with dichloroacetate, was evident within 13C NMR spectra of intact hearts as a relative increase in signal intensity of 53-62% (p less than 0.05) from the 4-carbon resonance of 13C-enriched glutamate when compared to the unaffected alanine signal. The increased bulk flow of [3-13C]pyruvate into the tricarboxylic acid cycle in response to dichloroacetate resulted in elevated fractional enrichment of glutamate from 68% in controls to 83% in the treated group (p less than 0.04), via interconversion with alpha-ketoglutarate, without changes in the actual tissue content of glutamate. Evidence of metabolic heterogeneity of cytosolic and mitochondrial pyruvate pools was also obtained from analysis of tissue extracts with in vitro NMR spectroscopy.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed2000

A model of inositol compartmentation in astrocytes based upon efflux kinetics and slow inositol depletion after uptake inhibition.

Intracellular compartmentation of inositol was demonstrated in primary cultures of mouse astrocytes, incubated in isotonic medium, by determination of efflux kinetics after "loading" with [3H]inositol. Three kinetically different compartments were delineated. The largest and most slowly exchanging compartment had a halflife of approximately 9 hr. This slow release leads to retention of a sizeable amount of pre-accumulated inositol in the tissue 24 hr after the onset of uptake inhibition, as confirmed by the observation that the inositol uptake inhibitor fucose caused a larger inhibition of unidirectional inositol uptake than of inositol pool size, measured as accumulated [3H]inositol after 24 hr of combined exposure to the inhibitor and the labeled isotope. Based upon the present observations and literature data, it is suggested that the large, slowly exchanging compartment is largely membrane-associated and participating in signaling via the phosphatidylinositide second messenger system, whereas inositol functioning as an osmolyte is distributed in the cytosol and located in one or both of the compartments showing a faster release.

Animals↗
PubMedDate not supplied

A comparative survey of automated parameter-search methods for compartmental neural models.

One of the most difficult and time-consuming aspects of building compartmental models of single neurons is assigning values to free parameters to make models match experimental data. Automated parameter-search methods potentially represent a more rapid and less labor-intensive alternative to choosing parameters manually. Here we compare the performance of four different parameter-search methods on several single-neuron models. The methods compared are conjugate-gradient descent, genetic algorithms, simulated annealing, and stochastic search. Each method has been tested on five different neuronal models ranging from simple models with between 3 and 15 parameters to a realistic pyramidal cell model with 23 parameters. The results demonstrate that genetic algorithms and simulated annealing are generally the most effective methods. Simulated annealing was overwhelmingly the most effective method for simple models with small numbers of parameters, but the genetic algorithm method was equally effective for more complex models with larger numbers of parameters. The discussion considers possible explanations for these results and makes several specific recommendations for the use of parameter searches on neuronal models.

Action Potentials↗
PubMed2001

Immunohistochemical evidence and ultrastructural compartmentalization of a new antioxidant enzyme in the rat substantia nigra.

We previously described in the rat the presence of dehydroascorbate reductase, an enzyme regenerating ascorbic acid, which is constantly lost during oxidative processes occurring at a fast rate within the central nervous system. In the present study, we specifically evaluate the occurrence of this enzyme in the rat substantia nigra by using immunohistochemistry, and by analyzing the neuronal compartmentalization of dehydroascorbate reductase within nigral neurons by immunoblotting and transmission electron microscopy coupled with immunocytochemistry. The enzyme occurs in various portions of the substantia nigra, but it is more abundant in the ventromedial part extending through the ventral tegmental area, and the dorsal portion, involving the pars compacta. Within nigral neurons, the cytosolic enzyme is present in a perinuclear position, close to mitochondria, and in the nuclear membrane; we also found the enzyme in nigral axons close to the myelin sheath. In addition, dehydroascorbate reductase was present in the nucleus of nigral neurons. The nuclear occurrence of the enzyme was confirmed by immunocytochemical labelling and immunoblotting of isolated nuclei. The nuclear enzyme was constantly evident as clusters of immunogold particles on chromatin. This localization suggests new roles for dehydroascorbate reductase (eg. prevention of DNA oxidative damage and regulation of gene transcription).

Animals↗
PubMed2004

Building biosynthetic schools: reviewing compartmentation of CNS taurine synthesis.

Taurine is one of the mammalian brain's most abundant and indispensable amino acids. Considerable strides have been made in understanding taurine biosynthesis within the brain, but many disputed issues nonetheless remain. Heading the list is the cellular origin of biosynthetically derived taurine: glial or neuronal? This article reviews the competing theories surrounding cellular compartmentation of taurine biosynthesis in the brain. It concludes that while in vitro systems clearly show astrocytes to be fully capable of taurine synthesis and neurons to be limited to synthesizing taurine from hypotaurine, there is insufficient evidence to attribute these processes to any one cell type in vivo. Instead, there is a growing body of evidence that suggests brain taurine biosynthesis is occurring via a more cooperative metabolic interaction between astrocytes and neurons.

Animals↗
PubMed2003

Viewpoint: therapeutic implications of CTLA-4 compartmentalization.

Understanding the regulatory events involved in the activation and inactivation of T cells is crucial to develop therapeutic approaches for autoimmune diseases and for organ transplantation. Co-stimulatory signals delivered through the CD28 receptor and inhibitory signals through CTLA-4 are required for the proper modulation of T cell responses and the induction and maintenance of peripheral tolerance. Manipulation of these signals is emerging as a potential strategy to prevent allograft rejection in different animal models. Recent data on the compartmentalization and the structural features of CTLA-4 within T cells provides critical information not only on the molecular basis of T cell inactivation by CTLA-4, but also on the key requirements for the successful development of therapeutic strategies targeting this molecule.

Antigens, CD↗
PubMed2006

Introns and the origin of nucleus-cytosol compartmentalization.

The origin of the eukaryotic nucleus marked a seminal evolutionary transition. We propose that the nuclear envelope's incipient function was to allow mRNA splicing, which is slow, to go to completion so that translation, which is fast, would occur only on mRNA with intact reading frames. The rapid, fortuitous spread of introns following the origin of mitochondria is adduced as the selective pressure that forged nucleus-cytosol compartmentalization.

Biological Evolution↗
PubMed2006

Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling.

A healthy individual can mount an immune response to exogenous pathogens while avoiding an autoimmune attack on normal tissues. The ability to distinguish between self and non-self is called 'immunological tolerance' and, for T lymphocytes, involves the generation of a diverse pool of functional T cells through positive selection and the removal of overtly self-reactive thymocytes by negative selection during T-cell ontogeny. To elucidate how thymocytes arrive at these cell fate decisions, here we have identified ligands that define an extremely narrow gap spanning the threshold that distinguishes positive from negative selection. We show that, at the selection threshold, a small increase in ligand affinity for the T-cell antigen receptor leads to a marked change in the activation and subcellular localization of Ras and mitogen-activated protein kinase (MAPK) signalling intermediates and the induction of negative selection. The ability to compartmentalize signalling molecules differentially in the cell endows the thymocyte with the ability to convert a small change in analogue input (affinity) into a digital output (positive versus negative selection) and provides the basis for establishing central tolerance.

Animals↗
PubMed1980

Validity of the digitonin method for metabolite compartmentation in isolated hepatocytes.

1. A modification of the digitonin method of Zuurendonk & Tager (1974) (Biochim. Biophys. Acta 333, 393-399) (i.e. the 'convaentional' method) was developed that allows the fractionation of isolated hepatocytes at -5 degrees C (i.e. 'low-temperature' method). 2. With respect to compartmentation of adenine nucleotides, glutamate and citrate, the two methods yielded very similar results. 3. In contrast, the mitochondrial amounts of aspartate and malate, as revealed by the low-temperature method, were about twice as high as those found by the conventional procedure. No change in the total cellular content occurred. 4. With n-butylmalonate and glisoxepid present in the conventional digitonin medium, significantly higher amounts of malate and aspartate respectively were found in the mitochondrial pellets. The results obtained by the low-temperature method, however, were not influenced by the these inhibitors. 5. It is concluded that under the conventional conditions of cell fractionation no appreciable redistribution of adenine nucleotides, glutamate and citrate occurs.

Adenine Nucleotides↗
PubMed1983

Evidence for the compartmentation of pyruvate metabolism in perfused rat skeletal muscle.

In rat hindlimbs perfused with [1-14C]pyruvate and 5 mM-dichloroacetate, the calculated apparent rate of pyruvate decarboxylation was decreased with increasing perfusate pyruvate concentrations. However, in the absence of dichloroacetate the apparent rate of decarboxylation increased under these conditions. Dichloroacetate enhanced [1-14C]pyruvate uptake, but decreased the specific radioactivity of effluent lactate. Glycogen metabolism remained unaffected. The results were not consistent with a common pyruvate pool, but provide evidence for the compartmentation of pyruvate metabolism.

Animals↗
PubMed1986

Compartmentation of guanine nucleotide precursors for DNA synthesis.

We have studied the kinetics of guanine incorporation into DNA in mouse T-lymphoma (S-49) mutant cells [PNPase (purine-nucleoside phosphorylase)- and HGPRTase (hypoxanthine: guanine phosphoribosyltransferase)-deficient] that are incapable of converting dGuo (deoxyguanosine) to Gua (guanine) ribonucleotides. Of the two possible pathways for an exogenous guanine source to reach DNA, firstly: dGuo----dGMP----dGDP----dGTP and secondly: Gua----GMP----GDP----dGDP----dGTP only the second pathway was found to be functional in providing guanine for DNA replication, although deoxyguanosine readily produced toxic cellular dGTP levels via the first pathway. The functional guanine-nucleotide-precursor pools for DNA are rather small; further, the depletion of the small GMP pool, but not that of GDP, GTP and dGTP, correlated well with the inhibition of DNA synthesis by mycophenolic acid, an IMP dehydrogenase inhibitor. These results support the hypothesis that guanine-nucleotide incorporation into DNA is highly compartmentalized and that a small functional guanine-nucleotide pool, e.g., the GMP pool, may serve a crucial role in limiting the availability of DNA precursor substrate.

Animals↗
PubMed1987

Compartmentalization of proline pools and apparent rates of collagen and non-collagen protein synthesis in arterial smooth muscle cells in culture.

Rates of collagen and non-collagen protein synthesis in rabbit arterial smooth muscle cells (SMC) were determined by using the specific (radio)activity of [3H]proline in the extracellular, intracellular, and prolyl-tRNA pools. The intracellular free proline specific activity was only 25% of the extracellular value in cultures incubated for 12 h in 0.25 mM-proline. The specific activity of prolyl-tRNA was less than 10% of the extracellular specific activity. Increasing the extracellular proline concentration 10-fold (to 2.5 mM), while keeping the extracellular specific activity of proline constant, resulted in equilibration of the specific activities of intracellular and extracellular free proline, but the specific activity of prolyl-tRNA remained at less than 10% of the extracellular specific activity. Therefore, calculated rates of collagen and non-collagen protein synthesis were greatly underestimated using the intracellular or extracellular specific activity of proline. SMC were also incubated with 0.1 mM-[14C]ornithine in 0.25 nM or 2.5 mM non-labelled proline to examine synthesis de novo of proline and prolyl-tRNA from ornithine. In SMC cultures containing 0.25 mM unlabelled proline, the specific activity of intracellular ornithine was approx. 45% of the extracellular specific activity, due to the production of unlabelled ornithine. The specific activity of ornithine-derived intracellular free proline in SMC incubated with 2.5 mM-proline was significantly lower than in SMC incubated in 0.25 mM-proline, due to the influx of unlabelled proline. However, a corresponding difference in the specific activity of [14C]prolyl-tRNA between SMC in 0.25 mM- or 2.5 mM-proline was not observed. Ornithine-derived [14C]proline was incorporated into proteins in a manner different from that of exogenously added radiolabelled proline. A much higher proportion of the proline synthesized de novo was channelled into collagen synthesis relative to total protein synthesis. Together, these results show that intracellular proline pools are highly compartmentalized in arterial SMC. They also suggest that proline synthesized from ornithine may enter a prolyl-tRNA pool separate from that of proline entering from the extracellular medium.

Animals↗
PubMed2002

Lipid rafts and little caves. Compartmentalized signalling in membrane microdomains.

Lipid rafts are liquid-ordered membrane microdomains with a unique protein and lipid composition found on the plasma membrane of most, if not all, mammalian cells. A large number of signalling molecules are concentrated within rafts, which have been proposed to function as signalling centres capable of facilitating efficient and specific signal transduction. This review summarizes current knowledge regarding the composition, structure, and dynamic nature of lipid rafts, as well as a number of different signalling pathways that are compartmentalized within these microdomains. Potential mechanisms through which lipid rafts carry out their specialized role in signalling are discussed in light of recent experimental evidence.

Animals↗
PubMed1996

Compartmentalized distribution of the proteins controlling the prespore-specific transcription factor sigmaF of Bacillus subtilis.

BACKGROUND: Differential gene expression during sporulation in the prespore and mother cell of Bacillus subtilis is dependent on the correct timing and localization of the activity of specific transcription (sigma) factors. The first sigma factor activated is sigmaF, which directs gene expression specifically in the prespore compartment. Release of sigmaF activity is tightly controlled through a series of complex interactions involving an anti-sigma factor, SpoIIAB, an anti-anti-sigma factor SpoIIAA and a phosphoprotein phosphatase SpoIIE. In vitro studies have shown that SpoIIAB binds to sigmaF, preventing transcription of the sigmaF regulon, and that it can also phosphorylate SpoIIAA, thereby inactivating it. However, non-phosphorylated SpoIIAA can displace sigmaF from SpoIIAB. The SpoIIE phosphatase provides a means of reactivating SpoIIAA-P. RESULTS: We have directly determined the cellular distributions of sigmaF, SpoIIAB, SpoIIAA-P and SpoIIAA during sporulation, using recently developed immunofluorescence methods. While sigmaF activity is restricted to the prespore, the protein is present in both compartments. As development proceeds the sigmaF signal disappears. The anti-sigma factor SpoIIAB is also distributed throughout both cells and rapidly disappears from both cellular compartments soon after sigmaF becomes active. Disappearance of SpoIIAB seems to be closely associated with the activation of the second prespore-specific sigma factor sigmaF. The distribution of phosphorylated SpoIIAA closely mimics that of SpoIIAB, being non-compartmentalized and disappearing soon after sigmaF activation occurs. Significantly, the active, non-phosphorylated form of the anti-anti-sigma factor, SpoIIAA, accumulates in the prespore just before sigmaF becomes active. CONCLUSION: These results support the hypothesis that the accumulation of SpoIIAA within the prespore is the single most important requirement for activation of sigmaF.

Bacillus subtilis↗