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781.
Phospholipid binding by a synaptic vesicle protein homologous to the regulatory region of protein kinase C 总被引:43,自引:0,他引:43
Neurotransmitters are released at synapses by the Ca2(+)-regulated exocytosis of synaptic vesicles, which are specialized secretory organelles that store high concentrations of neurotransmitters. The rapid Ca2(+)-triggered fusion of synaptic vesicles is presumably mediated by specific proteins that must interact with Ca2+ and the phospholipid bilayer. We now report that the cytoplasmic domain of p65, a synaptic vesicle-specific protein that binds calmodulin contains an internally repeated sequence that is homologous to the regulatory C2-region of protein kinase C (PKC). The cytoplasmic domain of recombinant p65 binds acidic phospholipids with a specificity indicating an interaction of p65 with the hydrophobic core as well as the headgroups of the phospholipids. The binding specificity resembles PKC, except that p65 also binds calmodulin, placing the C2-regions in a context of potential Ca2(+)-regulation that is different from PKC. This is a novel homology between a cellular protein and the regulatory domain of protein kinase C. The structure and properties of p65 suggest that it may have a role in mediating membrane interactions during synaptic vesicle exocytosis. 相似文献
782.
The identification and suppression of inherited neurodegeneration in Caenorhabditis elegans 总被引:14,自引:0,他引:14
The dominant mutation deg-1(u38) results in a toxic gene product that leads to the late-onset degeneration of a small number of neurons in the nematode Caenorhabditis elegans. Both intragenic and extragenic mutations as well as changes in wild-type gene dosage can delay or block the time of onset of the neuronal deaths. The deg-1 gene has been cloned and a partial complementary DNA reveals that the gene encodes a novel protein that may act as a membrane receptor. Because the late-onset loss of specific sets of neurons, often as a result of dominant mutations, is characteristic of several human neurodegenerative diseases, the analysis of the deg-1 gene and its suppressors may provide a means of understanding the mechanisms underlying some of these human diseases. 相似文献
783.
Co-localization of molecules involved in antigen processing and presentation in an early endocytic compartment 总被引:21,自引:0,他引:21
L E Guagliardi B Koppelman J S Blum M S Marks P Cresswell F M Brodsky 《Nature》1990,343(6254):133-139
The pathways of intracellular traffic involved in antigen processing and presentation have been defined by immunoelectron microscopy. The export pathway for class II histocompatibility molecules and the antigen import pathway meet in a peripheral endocytic compartment having all the molecular machinery believed to be required for antigen processing and presentation, including internalized surface immunoglobulins, proteolytic enzymes and invariant chains. This compartment defines a site where peptides from endocytosed antigen can bind class II molecules en route to the cell surface for presentation to T cells. 相似文献
784.
More false-positive problems 总被引:9,自引:0,他引:9
785.
In animals with internal fertilization, paternity is uncertain. In birds, the occurrence of copulations outside the pair-bond has been documented in a number of species, but the extent to which these result in illegitimate young is largely unknown, and constitutes a major deficiency in our understanding of avian mating systems. The analysis of tandemly repeated sequences (minisatellites), has enhanced our ability to make individual identifications and paternity determinations. Here we describe the use of a bird minisatellite DNA probe in assigning paternity in natural populations of the monogamous willow warbler Phylloscopus trochilus and of the polygynous wood warbler Phylloscopus sibilatrix. In both species this probe detects a multiple locus pattern and a single locus that exhibits a variable number of tandem repeats. Although we observed intrusions by non-resident males into the territories of paired males and extra-pair copulations, no illegitimate offspring were detected among 176 young from 32 families of both species, implying that extra-pair copulations have little or no genetic impact. 相似文献
786.
Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. 总被引:53,自引:0,他引:53
D P Rich M P Anderson R J Gregory S H Cheng S Paul D M Jefferson J D McCann K W Klinger A E Smith M J Welsh 《Nature》1990,347(6291):358-363
The cystic fibrosis transmembrane conductance regulator (CFTR) was expressed in cultured cystic fibrosis airway epithelial cells and Cl- channel activation assessed in single cells using a fluorescence microscopic assay and the patch-clamp technique. Expression of CFTR, but not of a mutant form of CFTR (delta F508), corrected the Cl- channel defect. Correction of the phenotypic defect demonstrates a causal relationship between mutations in the CFTR gene and defective Cl- transport which is the hallmark of the disease. 相似文献
787.
Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. 总被引:46,自引:0,他引:46
Neovascularization is critical for the growth of tumours and is a dominant feature in a variety of angiogenic diseases such as diabetic retinopathy, haemangiomas, arthritis and psoriasis. Recognition of the potential therapeutic benefit of controlling unabated capillary growth has led to a search for safe and effective angiogenesis inhibitors. We report here the synthesis of a family of novel inhibitors that are analogues of fumagillin, a naturally secreted antibiotic of Aspergillus fumigatus fresenius. We first isolated this fungus from a contaminated culture of capillary endothelial cells. Purified fumagillin inhibited endothelial cell proliferation in vitro and tumour-induced angiogenesis in vivo; it also inhibited tumour growth in mice, but prolonged administration was limited because it caused severe weight loss. Synthesis of fumagillin analogues yielded potent angiogenesis inhibitors ('angioinhibins') which suppress the growth of a wide variety of tumours with relatively few side-effects. 相似文献
788.
Expression and characterization of the cystic fibrosis transmembrane conductance regulator. 总被引:36,自引:0,他引:36
R J Gregory S H Cheng D P Rich J Marshall S Paul K Hehir L Ostedgaard K W Klinger M J Welsh A E Smith 《Nature》1990,347(6291):382-386
Cystic fibrosis (CF) is a common lethal genetic disease that manifests itself in airway and other epithelial cells as defective chloride ion absorption and secretion, resulting at least in part from a defect in a cyclic AMP-regulated, outwardly-rectifying Cl- channel in the apical surface. The gene responsible for CF has been identified and predicted to encode a membrane protein termed the CF transmembrane conductance regulator (CFTR). Identification of a cryptic bacterial promoter within the CFTR coding sequence led us to construct a complementary DNA in a low-copy-number plasmid, thereby avoiding the deleterious effects of CFTR expression on Escherischia coli. We have used this cDNA to express CFTR in vitro and in vivo. Here we demonstrate that CFTR is a membrane-associated glycoprotein that can be phosporylated in vitro by cAMP-dependent protein kinase. Polyclonal and monoclonal antibodies directed against distinct domains of the protein immunoprecipitated recombinant CFTR as well as the endogenous CFTR in nonrecombinant T84 cells. Partial proteolysis fingerprinting showed that the recombinant and non-recombinant proteins are indistinguishable. These data, which establish several characteristics of the protein responsible for CF, will now enable CFTR function to be studied and will provide a basis for diagnosis and therapy. 相似文献
789.
790.
Different voltage-dependent thresholds for inducing long-term depression and long-term potentiation in slices of rat visual cortex 总被引:25,自引:0,他引:25
In the hippocampus and neocortex, high-frequency (tetanic) stimulation of an afferent pathway leads to long-term potentiation (LTP) of synaptic transmission. In the hippocampus it has recently been shown that long-term depression (LTD) of excitatory transmission can also be induced by certain combinations of synaptic activation. In most hippocampal and all neocortical pathways studied so far, the induction of LTP requires the activation of N-methyl-D-aspartate (NMDA) receptor-gated conductances. Here we report that LTD can occur in neurons of slices of the rat visual cortex and that the same tetanic stimulation can induce either LTP or LTD depending on the level of depolarization of the postsynaptic neuron. By applying intracellular current injections or pharmacological disinhibition to modify the depolarizing response of the postsynaptic neuron to tetanic stimulation, we show that the mechanisms of induction of LTD and LTP are both postsynaptic. LTD is obtained if postsynaptic depolarization exceeds a critical level but remains below a threshold related to NMDA receptor-gated conductances, whereas LTP is induced if this second threshold is reached. 相似文献