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P Schoch J G Richards P H?ring B Takacs C St?hli T Staehelin W Haefely H M?hler 《Nature》1985,314(6007):168-171
The most abundant inhibitory neurotransmitter in the central nervous system, gamma-aminobutyric acid (GABA), exerts its main effects via a GABAA receptor that gates a chloride channel in the subsynaptic membrane. These receptors can contain a modulatory unit, the benzodiazepine receptor, through which ligands of different chemical classes can increase or decrease GABAA receptor function. We have now visualized a GABAA receptor in mammalian brain using monoclonal antibodies. The protein complex recognized by the antibodies contained high- and low-affinity binding sites for GABA as well as binding sites for benzodiazepines, indicative of a GABAA receptor functionally associated with benzodiazepine receptors. As the pattern of brain immunoreactivity corresponds to the autoradiographical distribution of benzodiazepine binding sites, most benzodiazepine receptors seem to be part of GABAA receptors. Two constituent proteins were identified immunologically. Because the monoclonal antibodies cross-react with human brain, they provide a means for elucidating those CNS disorders which may be linked to a dysfunction of a GABAA receptor. 相似文献
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RIM1alpha is required for presynaptic long-term potentiation. 总被引:8,自引:0,他引:8
Pablo E Castillo Susanne Schoch Frank Schmitz Thomas C Südhof Robert C Malenka 《Nature》2002,415(6869):327-330
Two main forms of long-term potentiation (LTP)-a prominent model for the cellular mechanism of learning and memory-have been distinguished in the mammalian brain. One requires activation of postsynaptic NMDA (N-methyl d-aspartate) receptors, whereas the other, called mossy fibre LTP, has a principal presynaptic component. Mossy fibre LTP is expressed in hippocampal mossy fibre synapses, cerebellar parallel fibre synapses and corticothalamic synapses, where it apparently operates by a mechanism that requires activation of protein kinase A. Thus, presynaptic substrates of protein kinase A are probably essential in mediating this form of long-term synaptic plasticity. Studies of knockout mice have shown that the synaptic vesicle protein Rab3A is required for mossy fibre LTP, but the protein kinase A substrates rabphilin, synapsin I and synapsin II are dispensable. Here we report that mossy fibre LTP in the hippocampus and the cerebellum is abolished in mice lacking RIM1alpha, an active zone protein that binds to Rab3A and that is also a protein kinase A substrate. Our results indicate that the long-term increase in neurotransmitter release during mossy fibre LTP may be mediated by a unitary mechanism that involves the GTP-dependent interaction of Rab3A with RIM1alpha at the interface of synaptic vesicles and the active zone. 相似文献
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RIM1alpha forms a protein scaffold for regulating neurotransmitter release at the active zone. 总被引:16,自引:0,他引:16
Susanne Schoch Pablo E Castillo Tobias Jo Konark Mukherjee Martin Geppert Yun Wang Frank Schmitz Robert C Malenka Thomas C Südhof 《Nature》2002,415(6869):321-326
Neurotransmitters are released by synaptic vesicle fusion at the active zone. The active zone of a synapse mediates Ca2+-triggered neurotransmitter release, and integrates presynaptic signals in regulating this release. Much is known about the structure of active zones and synaptic vesicles, but the functional relation between their components is poorly understood. Here we show that RIM1alpha, an active zone protein that was identified as a putative effector for the synaptic vesicle protein Rab3A, interacts with several active zone molecules, including Munc13-1 (ref. 6) and alpha-liprins, to form a protein scaffold in the presynaptic nerve terminal. Abolishing the expression of RIM1alpha in mice shows that RIM1alpha is essential for maintaining normal probability of neurotransmitter release, and for regulating release during short-term synaptic plasticity. These data indicate that RIM1alpha has a central function in integrating active zone proteins and synaptic vesicles into a molecular scaffold that controls neurotransmitter release. 相似文献
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Benzodiazepine receptors resolved 总被引:1,自引:0,他引:1
To date, attempts to map the distribution and density of benzodiazepine receptors in the CNS have been dominated by radiohistochemical techniques with conventional receptor binding. Their limited resolution, however, prompted us to try an immunohistochemical approach. Purified GABA/benzodiazepine receptors, prepared from bovine cerebral cortex, have been used to raise monoclonal antibodies for this purpose. Immunoreactive sites in rat brain, spinal cord and retina as well as in bovine and post-mortem human brain were found to be concentrated on neuronal cell bodies and processes in those regions known to be innervated by GABAergic neurons. Electron microscopic analysis revealed a selective staining of axosomatic and axodendritic pre- and postsynaptic contacts. 相似文献
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Sabine Gröbner Evelyn Fritz Friederike Schoch Martin Schaller Alexander C. Berger Michael Bitzer Ingo B. Autenrieth 《Cellular and molecular life sciences : CMLS》2010,67(19):3331-3344
Enterococci are commensal organisms in the alimentary tract. However, they can cause a variety of life-threatening infections,
especially in nosocomial settings. We hypothesized that induction of cell death might enable these facultative pathogenic
bacteria to evade the innate immune response and to cause infections of their host. We demonstrate that E. faecium when exposed to lysozyme induces cell death in macrophages in vitro and in vivo. Flow cytometric analyses of J774A.1 macrophages
infected with E. faecium revealed loss of cell membrane integrity indicated by uptake of propidium iodide and decrease of the inner mitochondrial
transmembrane potential ΔΨm. Inhibition of caspases, treatment of macrophages with cytochalasin D, or rifampicin did not prevent cells from dying, suggesting
cell death mechanisms that are independent of caspase activation, bacterial uptake, and intracellular bacterial replication.
Characteristics of necrotic cell death were demonstrated by both lack of procaspase 3 activation and cell shrinkage, electron
microscopy, and release of lactate dehydrogenase. Pretreatment of E. faecium with lysozyme and subsequently with broad spectrum protease considerably reduced cell death, suggesting that a bacterial
surface protein is causative for cell death induction. Moreover, in a mouse peritonitis model we demonstrated that E. faecium induces cell death of peritoneal macrophages in vivo. Altogether, our results show that enterococci, under specific conditions
such as exposure to lysozyme, induce necrotic cell death in macrophages, which might contribute to disseminated infections
by these facultative pathogenic bacteria. 相似文献
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J. G. Richards P. Schoch H. Möhler W. Haefely 《Cellular and molecular life sciences : CMLS》1986,42(2):121-126
Summary To date, attempts to map the distribution and density of benzodiazepine receptors in the CNS have been dominated by radiohistochemical techniques with conventional receptor binding. Their limited resolution, however, prompted us to try an immunohistochemical approach. Purified GABA/benzodiazepine receptors, prepared from bovine cerebral cortex, have been used to raise monoclonal antibodies for this purpose. Immunoreactive sites in rat brain, spinal cord and retina as well as in bovine and post-mortem human brain were found to be concentrated on neuronal cell bodies and processes in those regions known to be innervated by GABAergic neurons. Electron microscopic analysis revealed a selective staining of axosomatic and axodendritic pre- and postsynaptic contacts. 相似文献
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James TY Kauff F Schoch CL Matheny PB Hofstetter V Cox CJ Celio G Gueidan C Fraker E Miadlikowska J Lumbsch HT Rauhut A Reeb V Arnold AE Amtoft A Stajich JE Hosaka K Sung GH Johnson D O'Rourke B Crockett M Binder M Curtis JM Slot JC Wang Z Wilson AW Schüssler A Longcore JE O'Donnell K Mozley-Standridge S Porter D Letcher PM Powell MJ Taylor JW White MM Griffith GW Davies DR Humber RA Morton JB Sugiyama J Rossman AY Rogers JD Pfister DH Hewitt D Hansen K Hambleton S Shoemaker RA Kohlmeyer J 《Nature》2006,443(7113):818-822
The ancestors of fungi are believed to be simple aquatic forms with flagellated spores, similar to members of the extant phylum Chytridiomycota (chytrids). Current classifications assume that chytrids form an early-diverging clade within the kingdom Fungi and imply a single loss of the spore flagellum, leading to the diversification of terrestrial fungi. Here we develop phylogenetic hypotheses for Fungi using data from six gene regions and nearly 200 species. Our results indicate that there may have been at least four independent losses of the flagellum in the kingdom Fungi. These losses of swimming spores coincided with the evolution of new mechanisms of spore dispersal, such as aerial dispersal in mycelial groups and polar tube eversion in the microsporidia (unicellular forms that lack mitochondria). The enigmatic microsporidia seem to be derived from an endoparasitic chytrid ancestor similar to Rozella allomycis, on the earliest diverging branch of the fungal phylogenetic tree. 相似文献
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