Investigation of the Mg2+ Blockade of the NMDA Receptor

NMDA 受体 Mg2 阻断的研究

• 批准号: 6837879
• 负责人: Ernest James Petersson
• 金额: $ 3.99万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2005-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6837879
• 关键词: CHO cells; NMDA receptors; Xenopus; binding sites; calcium channel; calcium ion; electrophysiology; glutamates; ligands; magnesium ion; molecular biology; neural degeneration; predoctoral investigator; protein binding; protein structure; tissue /cell culture

DESCRIPTION (provided by applicant): The N-methyl-D-aspartate receptor (NMDAR) is a ligand-gated ion channel protein whose function as a logic gate lies at the heart of the molecular processes of memory formation. At resting membrane potentials the presence of the glutamate ligand alone is insufficient to open the channel because its pore is blocked by Mg2+. Depolarization of the neuron removes the blockade, permitting calcium flow that initiates a strengthening of the synapse and memory formation. Excessive calcium flow through the NMDAR is believed to underlie neurodegeneration in ischemia, stroke, and several neurological diseases. Drug treatments must be able to tweak this essential protein's function back to normal. The development of such drugs requires a detailed understanding of the subtleties of the NMDAR. The NMDAR blockade site is unusual in that it is hydrophobic, rather than highly negatively charged, like most Mg2+-binding sites. We hope to dissect the Mg2+ blockade using a series of subtle and dramatic alterations to the protein structure through the site-specific incorporation of unnatural amino acids. We will functionally assay these chemical perturbations of the steric and electronic interactions with the Mg2+ cation through electrophysiology.

描述（由申请人提供）：N-甲基-D-天冬氨酸受体（NMDAR）是一种配体门控离子通道蛋白，其作为逻辑门的功能位于记忆形成分子过程的核心。在静息膜电位下，仅存在谷氨酸配体不足以打开通道，因为其孔被 Mg2+ 堵塞。神经元的去极化消除了封锁，允许钙流，从而启动突触和记忆形成的强化。据信，流经 NMDAR 的钙过多是缺血、中风和多种神经系统疾病中神经退行性病变的原因。药物治疗必须能够使这种必需蛋白质的功能恢复正常。此类药物的开发需要详细了解 NMDAR 的微妙之处。 NMDAR 封锁位点的不同寻常之处在于它是疏水性的，而不是像大多数 Mg2+ 结合位点那样带有高负电荷。我们希望通过非天然氨基酸的位点特异性掺入对蛋白质结构进行一系列微妙而戏剧性的改变来剖析 Mg2+ 封锁。我们将通过电生理学对 Mg2+ 阳离子的空间和电子相互作用的这些化学扰动进行功能分析。