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71.
Jimenez EC Shetty RP Lirazan M Rivier J Walker C Abogadie FC Yoshikami D Cruz LJ Olivera BM 《Journal of neurochemistry》2003,85(3):610-621
A new class of Conus peptides, the I-superfamily of conotoxins, has been characterized using biochemical, electrophysiological and molecular genetic methods. Peptides in this superfamily have a novel pattern of eight Cys residues. Five peptides that elicited excitatory symptomatology, r11a, r11b, r11c, r11d and r11e, were purified from Conus radiatus venom; four were tested on amphibian peripheral axons and shown to elicit repetitive action potentials, consistent with being members of the 'lightning-strike cabal' of toxins that effect instant immobilization of fish prey. A parallel analysis of Conus cDNA clones revealed a new class of conotoxin genes that was particularly enriched (with 18 identified paralogues) in a Conus radiatus venom duct library; several C. radiatus clones encoded the excitatory peptides directly characterized from venom. The remarkable diversity of related I-superfamily peptides within a single Conus species is unprecedented. When combined with the excitatory effects observed on peripheral circuitry, this unexpected diversity suggests a corresponding molecular complexity of the targeted signaling components in peripheral axons; the I-conotoxin superfamily should provide a rich lode of pharmacological tools for dissecting and understanding these. Thus, the I-superfamily conotoxins promise to provide a significant new technology platform for dissecting the molecular components of axons. 相似文献
72.
Beta(1)/beta(2)/beta(3)-adrenoceptor knockout mice are obese and cold-sensitive but have normal lipolytic responses to fasting 总被引:1,自引:0,他引:1
Jimenez M Léger B Canola K Lehr L Arboit P Seydoux J Russell AP Giacobino JP Muzzin P Preitner F 《FEBS letters》2002,530(1-3):37-40
Catecholamines are viewed as major stimulants of diet- and cold-induced thermogenesis and of fasting-induced lipolysis, through the β-adrenoceptors (β1/β2/β3). To test this hypothesis, we generated β1/β2/β3-adrenoceptor triple knockout (TKO) mice and compared them to wild type animals. TKO mice exhibited normophagic obesity and cold-intolerance. Their brown fat had impaired morphology and lacked responses to cold of uncoupling protein-1 expression. In contrast, TKO mice had higher circulating levels of free fatty acids and glycerol at basal and fasted states, suggesting enhanced lipolysis. Hence, β-adrenergic signalling is essential for the resistance to obesity and cold, but not for the lipolytic response to fasting. 相似文献
73.
Sakkas LI Xu B Artlett CM Lu S Jimenez SA Platsoucas CD 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(7):3649-3659
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76.
Identification of a dantrolene-binding sequence on the skeletal muscle ryanodine receptor 总被引:2,自引:0,他引:2
Paul-Pletzer K Yamamoto T Bhat MB Ma J Ikemoto N Jimenez LS Morimoto H Williams PG Parness J 《The Journal of biological chemistry》2002,277(38):34918-34923
Dantrolene is a drug that suppresses intracellular Ca(2+) release from sarcoplasmic reticulum (SR) in skeletal muscle and is used as a therapeutic agent in individuals susceptible to malignant hyperthermia. Although its precise mechanism of action has not been elucidated, we have identified the N-terminal region (amino acids 1-1400) of the skeletal muscle isoform of the ryanodine receptor (RyR1), the primary Ca(2+) release channel in SR, as a molecular target for dantrolene using the photoaffinity analog [(3)H]azidodantrolene. Here, we demonstrate that heterologously expressed RyR1 retains its capacity to be specifically labeled with [(3)H]azidodantrolene, indicating that muscle specific factors are not required for this ligand-receptor interaction. Synthetic domain peptides of RyR1 previously shown to affect RyR1 function in vitro and in vivo were exploited as potential drug binding site mimics and used in photoaffinity labeling experiments. Only DP1 and DP1-2s, peptides containing the amino acid sequence corresponding to RyR1 residues 590-609, were specifically labeled by [(3)H]azidodantrolene. A monoclonal anti-RyR1 antibody that recognizes RyR1 and its 1400-amino acid N-terminal fragment recognizes DP1 and DP1-2s in both Western blots and immunoprecipitation assays and specifically inhibits [(3)H]azidodantrolene photolabeling of RyR1 and its N-terminal fragment in SR. Our results indicate that synthetic domain peptides can mimic a native, ligand-binding conformation in vitro and that the dantrolene-binding site and the epitope for the monoclonal antibody on RyR1 are equivalent and composed of amino acids 590-609. 相似文献
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78.
Costa-Lotufo LV Jimenez PC Wilke DV Leal LK Cunha GM Silveira ER Canuto KM Viana GS Moraes ME de Moraes MO Pessoa C 《Zeitschrift für Naturforschung. C, Journal of biosciences》2003,58(9-10):675-680
Amburana cearensis a common tree found in Northeastern Brazil is widely used in folk medicine. The present work evaluated the cytotoxicity of kaempferol, isokaempferide, amburoside A and protocatechuic acid isolated from the ethanol extract of the trunk bark of A. cearensis. The compounds were tested for their cytotoxicity on the sea urchin egg development, hemolysis assay and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay using tumor cell lines. Isokaempferide and kaempferol, but not amburoside A and protocatechuic acid, inhibited the sea urchin egg development as well as tumor cell lines, but in this assay isokaempferide was more potent than kaempferol. Protocatechuic acid was the only compound able to induce hemolysis of mouse erythrocytes, suggesting that the cytotoxicity of kaempferol and isokaempeferide was not related to membrane damage. 相似文献
79.
We have previously shown that two histidine residues of the nicotinic acetylcholine receptor are relevant for alpha-bungarotoxin binding. This paper studies: (1) the interaction between alpha-bungarotoxin and the peptide alpha173-202--synthesized according to the sequence of the Torpedo californica receptor alpha subunit--and between the toxin and the same peptide containing His186 modified with ethoxyformic anhydride or substituted by Ala; (2) the influence of the presence of Cys192-Cys193 disulfide bridge on such interactions. Solid-phase and in-solution competition assays were performed: ethoxyformylation of His186 or its substitution by Ala led to a significant drop in the toxin binding capacity only for peptides containing the bridge. Circular dichroism and fourth derivate spectra of all peptides were also analyzed. Results strongly indicate the involvement of His186 in the toxin binding to those peptides with the bridge--also present in the native receptor molecules--but not to their reduced forms; on the other hand, they give further support to the already established premise that, though the bridge does not participate directly in receptor-toxin binding, its presence is relevant to define the appropriate conformation of the interaction area. 相似文献
80.
Protein kinase CK2 is a heteromeric enzyme with catalytic (alpha) and regulatory (beta) subunits which form an alpha2beta2 holoenzyme and utilizes both ATP and GTP as nucleotide substrate. Site-directed mutagenesis of CK2alpha subunit was used to study this capacity to use GTP. Deletion of asparagine 118 (alpha(deltaN118)) or the mutant alphaN118E gives a 5-6-fold increase in apparent Km for GTP with little effect on the affinity for ATP. Mutants alphaN118A and alphaD120N did not alter significantly the Km for either nucleotide. CK2alphaN118 has an apparent Ki for inosine 5' triphosphate 5-fold higher than wild-type and is very heat labile. These studies complement recent crystallographic data indicating a role for CK2alpha asparagine 118 in binding the guanine base. 相似文献