HETEROGENEITY OF NMDA RECEPTORS IN BRAIN

大脑中 NMDA 受体的异质性

• 批准号: 3478179
• 负责人: DANIEL T MONAGHAN
• 金额: $ 8.8万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 1995-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3478179
• 关键词: NMDA receptors; acidity /alkalinity; affinity labeling; autoradiography; brain; chemical group; chemical kinetics; dizocilpine; fluorimetry; gel electrophoresis; glutamates; laboratory rat; molecular weight; neuroanatomy; neurogenesis; neuropharmacology; phencyclidine; photoactivation; piperazines; protein isoforms; protein structure function; receptor binding; receptor expression; temperature

The N-methyl-D-aspartate (NMDA) class of excitatory amino acid receptors have rapidly become an important, major area of research in neuroscience. NMDA receptors not only mediate and modulate neurotransmission at a vast number of CNS synapses, but also play a pivotal role in linking neuronal activity to synaptic plasticity during development and learning. NMDA receptors have also been shown to be a critical factor in a variety of pathological processes and have been suggested to be causal in Huntington's and Alzheimer's diseases, schizophrenia, autism, cerebral palsy, and epilepsy development. It is now becoming increasingly apparent that there are multiple populations of NMDA receptors. At physiological, toxicological, and biochemical levels of analysis, there is evidence that there are at least two distinct populations of NMDA receptors that differ in their anatomy, pharmacology, molecular composition, and development. In addition, radioligand binding studies indicate that there are at least two anatomically and pharmacologically-distinct binding site populations of NMDA recognition sites. Thus, NMDA receptors appear to be homologous to the other, genetically-related (Myers et al., 1989) ion-channel receptors (nicotinic, GABA-A, and glycine) in having multiple, genetically-related forms (isoforms or isoreceptors) which display differing distributions in the brain, differing developmental patterns of expression, and variations in agonist and antagonist sensitivities. NMDA receptor subtypes may have significant clinical implications, because the receptor form with the greater agonist sensitivity would be expected to be primarily responsible for the cell death resulting from modest elevations of extracellular glutamate following ischemia and hypoglycemia. The focus of this proposal is to identify the distinguishing properties of NMDA receptor subtypes and to determine how the differing measures of heterogeneity are inter-related. Quantitative autoradiography will be used to evaluate how the anatomically-distinct NMDA binding site populations differ in their physio-chemical ligand binding properties, their pharmacological properties, and their anatomical and ontological patterns of expression. These data are necessary for evaluating the correspondence between heterogeneity observed in physiological/toxicological studies and in radioligand binding studies. Anatomical and pharmacological properties of NMDA receptor proteins labelled by the photoaffinity ligand azido[3H]- MK801 will permit correlating NMDA receptor heterogeneity to that seen at the molecular level. Together these studies should provide a unifying classification and description of NMDA receptor subtypes. The identification of distinct receptor subpopulations is necessary not only for the understanding of NMDA receptor action but is also of fundamental relevance to the general area of NMDA-receptor mediated seizure activity and neurotoxicity. Only with the resolution of subtypes and their distinguishing properties, it is possible to determine their relative contributions to various aspects of normal and abnormal brain function and to develop subtype-specific antagonists that maximize protection while not interfering with normal functions.

N-甲基-D-天冬氨酸（NMDA）类兴奋性氨基酸受体 已经迅速成为神经科学研究的一个重要领域。 NMDA受体不仅在很大程度上介导和调节神经传递， 神经突触的数量，而且在连接神经元 活动对发育和学习过程中突触可塑性的影响。 NMDA 受体也已被证明是多种疾病中的关键因素， 并已被认为是亨廷顿病的病因 老年痴呆症、精神分裂症、自闭症、脑瘫， 癫痫发展 现在越来越明显的是， NMDA受体的数量。 在生理学、毒理学和 生化水平的分析，有证据表明，至少有 两个不同的NMDA受体群体，它们在解剖学上不同， 药理学、分子组成和发展。 此外，本发明还提供了一种方法， 放射性配体结合研究表明，至少有两个 解剖学和药理学上不同的结合位点群体 NMDA识别位点。 因此，NMDA受体似乎与 另一种是遗传相关的（Myers等，1989）离子通道受体 （烟碱，GABA-A和甘氨酸）在具有多个，遗传相关 形式（同种型或同种受体），其在细胞中显示不同的分布， 大脑，不同的表达发展模式， 激动剂和拮抗剂敏感性。 NMDA受体亚型可能具有 重要的临床意义，因为受体形式与 更大的激动剂敏感性将是主要负责 对于细胞死亡导致的适度升高细胞外 缺血和低血糖后的谷氨酸盐。 本提案的重点是确定 NMDA受体亚型，并确定如何不同的措施， 异质性是相互关联。 将使用定量放射自显影术 评估解剖学上不同的NMDA结合位点群体如何 它们的物理化学配体结合特性不同， 药理学特性及其解剖学和本体学模式 的表达。 这些数据对于评估对应性是必要的 在生理学/毒理学研究中观察到的异质性之间， 在放射性配体结合研究中。 解剖学和药理学特性 光亲和配体叠氮[3 H]-标记的NMDA受体蛋白 MK 801将允许将NMDA受体异质性与 分子水平。 这些研究应该提供一个统一的 NMDA受体亚型的分类和描述。 识别不同的受体亚群是必要的， 这不仅是为了了解NMDA受体的作用， 与NMDA受体介导的癫痫发作的一般领域的基本相关性 活性和神经毒性。 只有通过子类型及其 区别性质，可以确定它们的相对 对正常和异常脑功能的各个方面的贡献， 开发亚型特异性拮抗剂，使保护作用最大化， 干扰正常功能。