CONANTOKINS: NMDA RECEPTOR SUBTYPES AND EPILEPSY

contorkin -样肽超家族是一组独特的Conus肽。conantokin样肽的构象稳定性不是通过多重二硫交联实现的，而是通过翻译后修饰实现的。间隔三到四个氨基酸的谷氨酸残基被修饰为γ -羧谷氨酸（Gla）；该基序通过螯合Ca++在细胞外环境中稳定螺旋构象。康托酮类超家族的一个分支包括已知的唯一针对n-甲基- d -天冬氨酸（NMDA）受体的肽配体。所提出的工作的广泛焦点是鉴定靶向NMDA受体的conantokin样肽超家族成员，并评估靶向NMDA受体的超家族中肽的亚型选择性。由于一些conantokin（例如，conantokin- g和conantokin- r）先前已被证明是有效的抗惊厥药，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疗效联系起来。我们的目标是了解由美国政府提供的异常有利的保护指数的潜在机制

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.