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.

Conantokin样肽超家族是一组独特的圆锥形肽。 conantokin样肽的构象稳定性不是通过多种二硫键交联，而是通过翻译后修饰来实现的。每三个或四个氨基酸被修饰为γ-羧基谷氨酸（GLA）的谷氨酸残基。该基序将通过CA ++的螯合在细胞外环境中稳定螺旋构象。类似Conantokin的超家族的一个分支包括唯一已知针对N-甲基-D-天冬氨酸（NMDA）受体的肽配体。拟议的工作的广泛重点是鉴定针对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。由于先前已显示出几种圆锥形动物（例如Conantokin-G和Conantokin-R）是有效的抗惊厥药，因此我们计划将单个Conantokin的NMDA受体亚型选择性与观察到的抗惊厥药相关联。目的是了解由该指数提供的异常有利保护指数的基本机制 在动物模型中进行测试时，Conantokin肽是Fring的听力癫痫发作小鼠。一个 长期目的是不靶向NMDA受体的Conantokin样肽超家族的分支的功能表征。