RESUMO
omega-Conotoxins selective for N-type calcium channels are useful in the management of severe pain. In an attempt to expand the therapeutic potential of this class, four new omega-conotoxins (CVIA-D) have been discovered in the venom of the piscivorous cone snail, Conus catus, using assay-guided fractionation and gene cloning. Compared with other omega-conotoxins, CVID has a novel loop 4 sequence and the highest selectivity for N-type over P/Q-type calcium channels in radioligand binding assays. CVIA-D also inhibited contractions of electrically stimulated rat vas deferens. In electrophysiological studies, omega-conotoxins CVID and MVIIA had similar potencies to inhibit current through central (alpha(1B-d)) and peripheral (alpha(1B-b)) splice variants of the rat N-type calcium channels when coexpressed with rat beta(3) in Xenopus oocytes. However, the potency of CVID and MVIIA increased when alpha(1B-d) and alpha(1B-b) were expressed in the absence of rat beta(3), an effect most pronounced for CVID at alpha(1B-d) (up to 540-fold) and least pronounced for MVIIA at alpha(1B-d) (3-fold). The novel selectivity of CVID may have therapeutic implications. (1)H NMR studies reveal that CVID possesses a combination of unique structural features, including two hydrogen bonds that stabilize loop 2 and place loop 2 proximal to loop 4, creating a globular surface that is rigid and well defined.
Assuntos
Canais de Cálcio/metabolismo , Neurônios/metabolismo , ômega-Conotoxinas/metabolismo , Processamento Alternativo , Sequência de Aminoácidos , Animais , Sequência de Bases , Encéfalo/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Cromatografia Líquida de Alta Pressão , Clonagem Molecular , DNA Complementar/metabolismo , Relação Dose-Resposta a Droga , Eletrofisiologia , Ligação de Hidrogênio , Íons , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Modelos Moleculares , Dados de Sequência Molecular , Oócitos/metabolismo , Biossíntese Peptídica , Peptídeos/química , Ligação Proteica , Conformação Proteica , Isoformas de Proteínas , Estrutura Secundária de Proteína , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Homologia de Sequência de Aminoácidos , Homologia de Sequência do Ácido Nucleico , Caramujos , Fatores de Tempo , Ducto Deferente/metabolismo , Xenopus laevis , ômega-Conotoxinas/química , ômega-Conotoxinas/genética , ômega-Conotoxinas/farmacologiaRESUMO
The goal of this study was to investigate myelin phospholipids in vivo in multiple sclerosis lesions and normal-appearing white matter by evaluating the spectral broad component from phosphorus 31 magnetic resonance spectroscopic imaging data. The phospholipid broad component was reduced nearly 35% (p < 0.001) in both lesions and in normal-appearing white matter in multiple sclerosis subjects compared to control subjects, suggesting reduced myelin phospholipid concentration or altered relaxation times.
Assuntos
Espectroscopia de Ressonância Magnética , Esclerose Múltipla/metabolismo , Bainha de Mielina/metabolismo , Fosfolipídeos/metabolismo , Adulto , Membrana Celular/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , FósforoRESUMO
CFW female mice immunized with tobacco leaf extract developed type 1 skin and mast cell sensitivities that could be quantitated. The presence of both IgG1- and IgE-tobacco-mast-cell-sensitizing antibodies was detected by 2 and 48 h. PCA test. On the basis of these findings, it is suggested that mice can surve as good animal models for critical investigation of tobacco hypersensitivity in the laboratory.