CONANTOKINS: NMDA RECEPTOR SUBTYPES AND EPILEPSY

锥豆素：NMDA 受体亚型与癫痫

• 批准号: 6610790
• 负责人: BALDOMERO M OLIVERA
• 金额: $ 21.08万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6610790
• 关键词: NMDA receptors; anticonvulsants; conotoxin; electrophysiology; hippocampus; laboratory rat; ligands; neuropharmacology; pharmacokinetics; protein isoforms; protein structure function; receptor binding; reflex epilepsy; synapses; tissue /cell culture

The conantokin-like peptide superfamily is a distinctive group of Conus peptides. Conformational stability of the conantokin-like peptides is not achieved through multiple disulfide crosslinks, but rather by post-translational modification. Glutamate residues that are spaced every three or four amino acids are modified to gamma-carboxyglutamate (Gla); this motif would stabilize a helical conformation in the extracellular environment through chelation of Ca++. One branch of the conantokin-like superfamily comprises the only peptidic ligands known to be targeted to N-methyI-D-aspartate (NMDA) receptors. The broad focus of the proposed work is to identify the members of the conantokin-like peptide superfamily that are targeted to NMDA receptors, and to evaluate the subtype selectivity of peptides in the superfamily that do target NMDA receptors. Since several conantokins (e.g., conantokin-G and conantokin-R) have previously been shown to be potent anticonvulsants, we plan to correlate NMDA receptor subtype selectivity of an individual conantokin to the anticonvulsant efficacy observed. The goal is to understand the underlying mechanisms of the unusually favorable protective index afforded by the conantokin peptides when tested in an animal model, the Fring's audiogenic seizure mouse. A longer-term objective is a functional characterization of the branches of the conantokin-like peptide superfamily that do not target NMDA receptors.

芋螺毒素样肽超家族是芋螺肽的一个独特的群体。Conantokin样肽的构象稳定性不是通过多重二硫键交联实现的，而是通过翻译后修饰实现的。每三个或四个氨基酸间隔的谷氨酸残基被修饰为γ-羧基谷氨酸（Gla）;该基序将通过螯合Ca++稳定细胞外环境中的螺旋构象。刀豆毒素样超家族的一个分支包含已知靶向N-甲基-D-天冬氨酸（NMDA）受体的唯一肽配体。拟议的工作的广泛重点是确定靶向NMDA受体的Conantokin样肽超家族的成员，并评估靶向NMDA受体的超家族中肽的亚型选择性。由于几种芋螺毒素（例如，Conantokin-G和Conantokin-R）是有效的抗惊厥药，我们计划将单个Conantokin的NMDA受体亚型选择性与观察到的抗惊厥功效相关联。我们的目标是要了解的基本机制，异常有利的保护指数所提供的 当在动物模型Fring听源性癫痫小鼠中测试时，一 更长期的目标是对不靶向NMDA受体的芋螺毒素样肽超家族的分支进行功能表征。