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McKeown SC Corbett DF Goetz AS Littleton TR Bigham E Briscoe CP Peat AJ Watson SP Hickey DM 《Bioorganic & medicinal chemistry letters》2007,17(6):1584-1589
The discovery, synthesis and structure-activity relationship (SAR) of novel carboxylic acid agonists for GPR40 are described. Aryl propionic acid 1, identified from a high throughput screen, was selected for chemical exploration. Compound 2 was identified as our lead molecule through efficient solid phase combinatorial array chemistry and had an attractive in vitro and in vivo pharmacokinetic profile in rat. These ligands may prove useful in establishing a role for GPR40 in insulin regulation. 相似文献
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Is synaptotagmin the calcium sensor? 总被引:5,自引:0,他引:5
After much debate, recent progress indicates that the synaptic vesicle protein synaptotagmin I probably functions as the calcium sensor for synchronous neurotransmitter release. Following calcium influx into presynaptic terminals, synaptotagmin I rapidly triggers the fusion of synaptic vesicles with the plasma membrane and underlies the fourth-order calcium cooperativity of release. Biochemical and genetic studies suggest that lipid and SNARE interactions underlie synaptotagmin's ability to mediate the incredible speed of vesicle fusion that is the hallmark of fast synaptic transmission. 相似文献
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Carlton DL Collin-Smith LJ Daniels AJ Deaton DN Goetz AS Laudeman CP Littleton TR Musso DL Morgan RJ Szewczyk JR Zhang C 《Bioorganic & medicinal chemistry letters》2008,18(20):5451-5455
Starting from a weak omeprazole screening hit, replacement of the pyridine with a 1,3-benzodioxole moiety, modification of the thioether linkage, and substitution of the benzimidazole pharmacophore led to the discovery of nanomolar BRS-3 agonists. 相似文献
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David?N. Herrmann Rita Horvath Janet?E. Sowden Michael Gonzales Avencia Sanchez-Mejias Zhuo Guan Roger?G. Whittaker Jorge?L. Almodovar Maria Lane Boglarka Bansagi Angela Pyle Veronika Boczonadi Hanns Lochmüller Helen Griffin Patrick?F. Chinnery Thomas?E. Lloyd J.?Troy Littleton Stephan Zuchner 《American journal of human genetics》2014,95(3):332-339
Synaptotagmin 2 is a synaptic vesicle protein that functions as a calcium sensor for neurotransmission but has not been previously associated with human disease. Via whole-exome sequencing, we identified heterozygous missense mutations in the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two multigenerational families presenting with peripheral motor neuron syndromes. An essential calcium-binding aspartate residue, Asp307Ala, was disrupted by a c.920A>C change in one family that presented with an autosomal-dominant presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome. A c.923C>T variant affecting an adjacent residue (p.Pro308Leu) produced a presynaptic neuromuscular junction defect and a dominant hereditary motor neuropathy in a second family. Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis using this transgenic model. These findings indicate that Synaptotagmin 2 regulates neurotransmitter release at human peripheral motor nerve terminals. In addition, mutations in the Synaptotagmin 2 C2B domain represent an important cause of presynaptic congenital myasthenic syndromes and link them with hereditary motor axonopathies. 相似文献
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Edward Littleton Mathias Dreger Jackie Palace Angela Vincent 《Molecular & cellular proteomics : MCP》2009,8(7):1688-1696
There is increasing interest in the role of antibodies targeting specific membrane proteins in neurological and other diseases. The target(s) of these pathogenic antibodies is known in a few diseases, usually when candidate cell surface proteins have been tested. Approaches for identifying new antigens have mainly resulted in the identification of antibodies to intracellular proteins, which are often very useful as diagnostic markers for disease but unlikely to be directly involved in disease pathogenesis because they are not accessible to circulating antibodies. To identify cell surface antigens, we developed a “conformational membrane antigen isolation and identification” strategy. First, a cell line is identified that reacts with patient sera but not with control sera. Second, intact cells are exposed to sera to allow the binding of presumptive autoantibodies to their cell surface targets. After washing off non-bound serum components, the cells are lysed, and immune complexes are precipitated. Third, the bound surface antigen is identified by mass spectrometry. As a model system we used a muscle cell line, TE671, that endogenously expresses muscle-specific tyrosine receptor kinase (MuSK) and sera or plasmas from patients with a subtype of the autoimmune disease myasthenia gravis in which patients have autoantibodies against MuSK. MuSK was robustly detected as the only membrane protein in immunoprecipitates from all three patient samples tested and not from the three MuSK antibody-negative control samples processed in parallel. Of note, however, there were many intracellular proteins found in the immunoprecipitates from both patients and controls, suggesting that these were nonspecifically immunoprecipitated from cell extracts. The conformational membrane antigen isolation and identification technique should be of value for the detection of highly relevant antigenic targets in the growing number of suspected antibody-mediated autoimmune disorders. The approach would also be very suitable for the analysis of human or experimental antitumor responses.Autoimmune diseases are conditions in which aberrant immune responses cause damage to and dysfunction of the body''s own tissue. They range from prevalent conditions, such as type 1 diabetes mellitus and rheumatoid arthritis, to various types of autoimmune thyroiditis (1), inflammatory bowel diseases (2), skin conditions such as bullous pemphigoid (3), and rarer neurological disorders such as myasthenia gravis (4).Understanding of most of these diseases is still highly incomplete. Fundamental knowledge includes the identity of the antigenic target of the immune response and whether the response is predominantly T cell- or antibody-mediated. In some of the above examples, “candidate” antigens have been proposed as a result of study of the pathophysiology of the disease (e.g. see Ref. 5). The detection of a disease-specific autoantibody allows the development of diagnostic tests, and if the target is a cell surface protein it usually implies that the disease will respond clinically to treatments that reduce the levels of the pathogenic antibodies.In recent years, there has also been increasing interest in natural (or experimental) immune responses to tumor cells that may slow the growth or spread of a tumor. In some cases, however, this immune response may result in pathogenic autoimmunity. For example, antibodies directed to voltage-gated calcium channels expressed on the surface of small cell lung cancer cells can cause neurological dysfunction by binding to similar calcium channels on the motor nerve endings (see Ref. 4). In other cancer-associated (paraneoplastic) disorders, however, there are antibodies to intracellular antigens, which are also shared between the tumor and neuronal tissue, that are highly useful as diagnostic markers for the disorders. In these patients, T cell immunity is thought to be responsible for the neurological disease (see Ref. 6), which generally does not improve with immunosuppressive treatments.Attempts to identify autoantigens and tumor antigens in many autoimmune and cancer-related syndromes have generally used techniques involving screening of mRNA expression libraries or, more recently, separation of soluble extracts of tissue or cell lines by one- or two-dimensional electrophoresis and blotting of the separated proteins onto membranes where they are probed with patient sera. Typically in any one experiment, a large number of protein bands or spots are bound by serum antibodies, and some of the corresponding bands or spots on the gel are then excised, digested, and analyzed by mass spectrometry (e.g. Refs. 7 and 8). The identified proteins have been claimed as novel antigens associated with the condition with sometimes a whole array of proteins identified from a single experiment and claimed to represent a disease-associated “autoimmune profile.” However, the identified proteins are often common intracellular proteins with the same or closely related proteins repeatedly implicated in seemingly unrelated autoimmune, allergic, and malignant diseases (see “Discussion”). The intracellular location of these proteins where they would be inaccessible to circulating antibodies and their lack of disease specificity cast doubt upon their relevance.The best understood example of an antibody-mediated disease is myasthenia gravis with acetylcholine receptor antibodies (for a review, see Ref. 9). Another subgroup of myasthenia gravis patients has antibodies to a muscle-specific tyrosine kinase (MuSK).1 These antibodies are known to bind to the cell surface and to inhibit the clustering function of MuSK (10). Although the mechanisms of disease are not fully understood, the patients respond to immunotherapies, and the identification of this antigen by a candidate approach has revolutionized the diagnosis and treatment of this subtype of myasthenia (11). In many other conditions, however, no suitable candidate antigens have yet been proposed, limiting the diagnosis and treatment of the disorders.To develop a novel proteomics strategy for identifying cell membrane autoantigens, we used a model system involving antibodies from MuSK antibody-positive patients and from MuSK antibody-negative subjects. We first allowed the antibodies to bind to their target(s) on the intact cell surface, rather than after extraction and denaturation in detergents, so that the antibodies could recognize fully conformational epitopes. The cells, with antibodies already bound, were then solubilized, and the ready formed immune complexes were isolated and either visualized by SDS-PAGE and immunoblotting or identified by mass spectrometry. Although we show the current results as a “proof of principle,” the “conformational membrane antigen isolation and identification” (CMAII) technique could easily be adapted for use in studies of other diseases. 相似文献
48.
We describe the isolation and characterization of nwk (nervous wreck), a temperature-sensitive paralytic mutant that causes excessive growth of larval neuromuscular junctions (NMJs), resulting in increased synaptic bouton number and branch formation. Ultrastructurally, mutant boutons have reduced size and fewer active zones, associated with a reduction in synaptic transmission. nwk encodes an FCH and SH3 domain-containing adaptor protein that localizes to the periactive zone of presynaptic terminals and binds to the Drosophila ortholog of Wasp (Wsp), a key regulator of actin polymerization. wsp null mutants display synaptic overgrowth similar to nwk and enhance the nwk morphological phenotype in a dose-dependent manner. Evolutionarily, Nwk belongs to a previously undescribed family of adaptor proteins that includes the human srGAPs, which regulate Rho activity downstream of Robo receptors. We propose that Nwk controls synapse morphology by regulating actin dynamics downstream of growth signals in presynaptic terminals. 相似文献
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Synaptotagmin I functions as a calcium sensor to synchronize neurotransmitter release 总被引:9,自引:0,他引:9
To characterize Ca(2+)-mediated synaptic vesicle fusion, we analyzed Drosophila synaptotagmin I mutants deficient in specific interactions mediated by its two Ca(2+) binding C2 domains. In the absence of synaptotagmin I, synchronous release is abolished and a kinetically distinct delayed asynchronous release pathway is uncovered. Synapses containing only the C2A domain of synaptotagmin partially recover synchronous fusion, but have an abolished Ca(2+) cooperativity. Mutants that disrupt Ca(2+) sensing by the C2B domain have synchronous release with normal Ca(2+) cooperativity, but with reduced release probability. Our data suggest the Ca(2+) cooperativity of neurotransmitter release is likely mediated through synaptotagmin-SNARE interactions, while phospholipid binding and oligomerization trigger rapid fusion with increased release probability. These results indicate that synaptotagmin is the major Ca(2+) sensor for evoked release and functions to trigger synchronous fusion in response to Ca(2+), while suppressing asynchronous release. 相似文献