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Gunnar Pejler - One of the best experts on this subject based on the ideXlab platform.
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mast Cell secretory Granules armed for battle
2014Co-Authors: Sara Wernersson, Gunnar PejlerAbstract:Mast Cells are important effector Cells of the immune system and recent studies show that they have immunomodulatory roles in diverse processes in both health and disease. Mast Cells are distinguished by their high content of electron-dense secretory Granules, which are filled with large amounts of preformed and pre-activated immunomodulatory compounds. When appropriately activated, mast Cells undergo degranulation, a process by which these preformed Granule compounds are rapidly released into the surroundings. In many cases, the effects that mast Cells have on an immune response are closely associated with the biological actions of the Granule compounds that they release, as exemplified by the recent studies showing that mast Cell Granule proteases account for many of the protective and detrimental effects of mast Cells in various inflammatory settings. In this Review, we discuss the current knowledge of mast Cell secretory Granules.
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novel insights into the biological function of mast Cell carboxypeptidase a
2009Co-Authors: Gunnar Pejler, Frida Henningsson, Stefan D Knight, Sara WernerssonAbstract:When mast Cells are activated they can respond by releasing their secretory Granule compounds, including mast Cell-specific proteases of chymase, tryptase and carboxypeptidase A (MC-CPA) type. MC-CPA is a dominant protein component of the mast Cell Granule and the MC-CPA gene is extremely highly expressed. Despite this, relatively little has been known of its biological function. However, the recent generation of mouse strains lacking MC-CPA has opened up new possibilities for investigations related to this protease. This recent development has revealed a role for MC-CPA in regulating innate immunity responses, including the degradation of harmful substances such as the vasoconstrictive factor endothelin 1 and snake venom toxins. Here, we summarize the current knowledge of MC-CPA.
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reduction with dithiothreitol causes serglycin specific defects in secretory Granule integrity of bone marrow derived mast Cells
2009Co-Authors: Tiago Braga, Magnus Abrink, Maria Ringvall, Heidi Tveit, Gunnar PejlerAbstract:Mast Cell Granule maturation and storage of Granule components has previously been shown to be critically dependent on serglycin (SG), a proteoglycan abundantly stored in mast Cell secretory Granules. The N-terminal portion of serglycin contains a conserved disulfide motif that is similar to motifs found in secretory Granule compounds of neuroendocrine Cells. Interference with such motifs of neuroendocrine Cells with dithiothreitol (DTT) has previously been shown to cause Cellular missorting. To investigate the implication for serglycin, serglycin(+/+) and serglycin(-/-) bone marrow derived mast Cells (BMMCs) were treated with DTT followed by assessment of proteoglycan synthesis and secretory Granule integrity. Treatment of serglycin(+/+) BMMCs with DTT almost completely abolished biosynthetic incorporation of (35)S-sulfate into proteoglycans, caused a dramatic reduction of granular staining with May Grunwald/Giemsa as well as disruption of Granule dense core formation as shown by transmission electron microscopy. In addition, the storage of carboxypeptidase A, a major secretory Granule compound, was markedly reduced following DTT treatment. In contrast, none of these effects were seen after treatment of SG(-/-) BMMCs with DTT, indicating that they were serglycin-specific. Notably, DTT treated serglycin(+/+) BMMCs showed similar morphology as did the serglycin(-/-) BMMCs. DTT treatment affected neither the viability of the BMMCs nor the mRNA levels for serglycin or carboxypeptidase A. Together, these data indicate that DTT causes dramatic, serglycin-specific effects on mast Cell Granule. These findings are thus in accordance with a role for the N-terminal disulfide motif in serglycin for regulation of mast Cell secretory Granule integrity.
Peter Jonas - One of the best experts on this subject based on the ideXlab platform.
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a small number of open ca2 channels trigger transmitter release at a central gabaergic synapse
2010Co-Authors: Iancu Bucurenciu, Josef Bischofberger, Peter JonasAbstract:Previous work has suggested that triggering transmitter release might require the opening of many Ca2+ channels. Here the authors show that at the inhibitory basket Cell–Granule Cell synapse in rat hippocampus, the opening of three or fewer Ca2+ channels is sufficient to trigger transmitter release with high temporal precision.
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nanodomain coupling between ca2 channels and ca2 sensors promotes fast and efficient transmitter release at a cortical gabaergic synapse
2008Co-Authors: Iancu Bucurenciu, Akos Kulik, Beat Schwaller, Michael Frotscher, Peter JonasAbstract:Summary It is generally thought that transmitter release at mammalian central synapses is triggered by Ca 2+ microdomains, implying loose coupling between presynaptic Ca 2+ channels and Ca 2+ sensors of exocytosis. Here we show that Ca 2+ channel subunit immunoreactivity is highly concentrated in the active zone of GABAergic presynaptic terminals of putative parvalbumin-containing basket Cells in the hippocampus. Paired recording combined with presynaptic patch pipette perfusion revealed that GABA release at basket Cell-Granule Cell synapses is sensitive to millimolar concentrations of the fast Ca 2+ chelator BAPTA but insensitive to the slow Ca 2+ chelator EGTA. These results show that Ca 2+ source and Ca 2+ sensor are tightly coupled at this synapse, with distances in the range of 10–20 nm. Models of Ca 2+ inflow-exocytosis coupling further reveal that the tightness of coupling increases efficacy, speed, and temporal precision of transmitter release. Thus, tight coupling contributes to fast feedforward and feedback inhibition in the hippocampal network.
Arnold H. Greenberg - One of the best experts on this subject based on the ideXlab platform.
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purification of three cytotoxic lymphocyte Granule serine proteases that induce apoptosis through distinct substrate and target Cell interactions
1992Co-Authors: J C Powers, Ruedi Aebersold, Arnold H. GreenbergAbstract:We recently reported the purification of a lymphocyte Granule protein called "fragmentin," which was identified as a serine protease with the ability to induce oligonucleosomal DNA fragmentation and apoptosis (Shi, L., R. P. Kraut, R. Aebersold, and A. H. Greenberg. 1992. J. Exp. Med. 175:553). We have now purified two additional proteases with fragmentin activity from lymphocyte Granules. The three proteases are of two types; one has the unusual ability to cleave a tripeptide thiobenzyl ester substrate after aspartic acid, similar to murine cytotoxic Cell protease I/granzyme B, while two are tryptase-like, preferentially hydrolyzing after arginine, and bear some homology to human T Cell Granule tryptases, granzyme 3, and Hanukah factor/granzyme A. Using tripeptide chloromethyl ketones, the pattern of inhibition of DNA fragmentation corresponded to the inhibition of peptide hydrolysis. The Asp-ase fragmentin was blocked by aspartic acid-containing tripeptide chloromethyl ketones, while the tryptase fragmentins were inhibited by arginine-containing chloromethyl ketones. The two tryptase fragmentins were slow acting and were partly suppressed by blocking proteins synthesis with cycloheximide in the YAC-1 target Cell. In contrast, the Asp-ase fragmentin was fast acting and produced DNA damage in the absence of protein synthesis. Using a panel of unrelated target Cells of lymphoma, thymoma, and melanoma origin, distinct patterns of sensitivity to the three fragmentins were observed. Thus, these three Granule proteases make up a family of fragmentins that activate DNA fragmentation and apoptosis by acting on unique substrates in different target Cells.
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a natural killer Cell Granule protein that induces dna fragmentation and apoptosis
1992Co-Authors: Lianfa Shi, R P Kraut, R Aebersold, Arnold H. GreenbergAbstract:We report the purification from a rat natural killer (RNK) large granular lymphocyte leukemia of a 32-kD Granule protein that induces rapid DNA fragmentation and apoptosis. The protein, which we have called "fragmentin," was capable of causing DNA from intact YAC-1 Cells to be cleaved into oligonucleosomal-sized fragments and producing severe chromatin condensation within 1 h. Amino acid sequence of tryptic peptides indicated that fragmentin was highly homologous to the NK and T Cell Granule serine proteases RNK protease 1 and mouse cytotoxic T Cell protease I (CCPI)/granzyme B. Preincubation with the serine esterase inhibitor 3,4-dichloroisocoumarin blocked fragmentin-induced DNA damage, but had no effect on cytolysin. Fragmentin activity against four lymphoma target Cells was completely dependent on the presence of cytolysin. Fragmentin produced rapid membrane damage as well as DNA fragmentation at nonlytic cytolysin doses, suggesting that fragmentin activity was not limited to its effects on the nucleus. Fragmentin and cytolysin activity were completely inhibited by EGTA, indicating the process was Ca2+ dependent. A role for cytolysin in endocytosis of fragmentin was suggested by the observation that treatment of YAC-1 with cytochalasin B or sodium azide and 2-deoxyglucose blocked DNA fragmentation but not cytolysin activity. A 30-kD N alpha-CBZ-L-lysine thiobenzyl esterase, which copurified with fragmentin, was inactive on its own but was able to synergistically amplify the DNA damage induced by fragmentin in the presence of cytolysin. Fragmentin activity was not dependent on protein synthesis, as cycloheximide treatment of YAC-1 Cells did not prevent DNA damage. We postulate that fragmentin is the molecular mediator of NK Cell-mediated DNA fragmentation and apoptosis.
Paola Rossi - One of the best experts on this subject based on the ideXlab platform.
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golgi Cell mediated activation of postsynaptic gabab receptors induces disinhibition of the golgi Cell Granule Cell synapse in rat cerebellum
2012Co-Authors: Federico Brandalise, Urs Gerber, Paola RossiAbstract:In the cerebellar glomerulus, GABAergic synapses formed by Golgi Cells regulate excitatory transmission from mossy fibers to Granule Cells through feed-forward and feedback mechanisms. In acute cerebellar slices, we found that stimulating Golgi Cell axons with a train of 10 impulses at 100 Hz transiently inhibited both the phasic and the tonic components of inhibitory responses recorded in Granule Cells. This effect was blocked by the GABAB receptor blocker {"type":"entrez-protein","attrs":{"text":"CGP35348","term_id":"875599329","term_text":"CGP35348"}}CGP35348, and could be mimicked by bath-application of baclofen (30 µM). This depression of IPSCs was prevented when Granule Cells were dialyzed with GDPβS. Furthermore, when synaptic transmission was blocked, GABAA currents induced in Granule Cells by localized muscimol application were inhibited by the GABAB receptor agonist baclofen. These findings indicate that postsynaptic GABAB receptors are primarily responsible for the depression of IPSCs. This inhibition of inhibitory events results in an unexpected excitatory action by Golgi Cells on Granule Cell targets. The reduction of Golgi Cell-mediated inhibition in the cerebellar glomerulus may represent a regulatory mechanism to shift the balance between excitation and inhibition in the glomerulus during cerebellar information processing.
Iancu Bucurenciu - One of the best experts on this subject based on the ideXlab platform.
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a small number of open ca2 channels trigger transmitter release at a central gabaergic synapse
2010Co-Authors: Iancu Bucurenciu, Josef Bischofberger, Peter JonasAbstract:Previous work has suggested that triggering transmitter release might require the opening of many Ca2+ channels. Here the authors show that at the inhibitory basket Cell–Granule Cell synapse in rat hippocampus, the opening of three or fewer Ca2+ channels is sufficient to trigger transmitter release with high temporal precision.
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nanodomain coupling between ca2 channels and ca2 sensors promotes fast and efficient transmitter release at a cortical gabaergic synapse
2008Co-Authors: Iancu Bucurenciu, Akos Kulik, Beat Schwaller, Michael Frotscher, Peter JonasAbstract:Summary It is generally thought that transmitter release at mammalian central synapses is triggered by Ca 2+ microdomains, implying loose coupling between presynaptic Ca 2+ channels and Ca 2+ sensors of exocytosis. Here we show that Ca 2+ channel subunit immunoreactivity is highly concentrated in the active zone of GABAergic presynaptic terminals of putative parvalbumin-containing basket Cells in the hippocampus. Paired recording combined with presynaptic patch pipette perfusion revealed that GABA release at basket Cell-Granule Cell synapses is sensitive to millimolar concentrations of the fast Ca 2+ chelator BAPTA but insensitive to the slow Ca 2+ chelator EGTA. These results show that Ca 2+ source and Ca 2+ sensor are tightly coupled at this synapse, with distances in the range of 10–20 nm. Models of Ca 2+ inflow-exocytosis coupling further reveal that the tightness of coupling increases efficacy, speed, and temporal precision of transmitter release. Thus, tight coupling contributes to fast feedforward and feedback inhibition in the hippocampal network.