HETEROGENEITY OF NMDA RECEPTORS IN BRAIN

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的主要领域。 NMDA受体不仅在很大程度上介导和调节神经传递 中枢神经系统突触的数量，也在连接神经元的过程中起着举足轻重的作用 发育和学习过程中对突触可塑性的影响。NMDA 受体也被证明是多种疾病的关键因素。 病理过程，并已被认为是亨廷顿病的原因 阿尔茨海默氏症，精神分裂症，自闭症，脑瘫，以及 癫痫的发展。 现在越来越明显的是，有多个 NMDA受体的种群。在生理学、毒物学和 生化水平的分析，有证据表明至少有 两个截然不同的NMDA受体种群，它们的解剖结构不同， 药理学、分子组成和发展。此外, 放射性配基结合研究表明，至少有两种 在解剖学和药理学上不同的结合位点群体 NMDA识别站点。因此，NMDA受体似乎与 另一种是遗传相关的离子通道受体(Myers等人，1989) (尼古丁、GABA-A和甘氨酸)具有多个遗传相关 表现出不同分布的形式(异构体或同功受体) 大脑，表达的不同发育模式和变异 在激动剂和拮抗剂的敏感性上。NMDA受体亚型可能有 重要的临床意义，因为受体的形式与 更高的激动剂敏感性预计将是主要原因 对于细胞外适度升高导致的细胞死亡 缺血和低血糖后的谷氨酸。 本提案的重点是确定以下各项的区别属性 NMDA受体亚型，并确定不同的测量方法 异质性是相互关联的。将使用定量放射自显影 为了评估解剖上不同的NMDA结合位点群体 它们的物理化学配体结合性质不同，它们的 药理特性及其解剖学和本体论模式 表达的方式。这些数据是评估通信所必需的 在生理/毒理学研究中观察到的异质性和 在放射性配基结合研究中。解剖学和药理学特性 光亲和配基叠氮[~3H]标记的NMDA受体蛋白- MK801将允许将NMDA受体的异质性与 分子水平。总之，这些研究应该提供一个统一的 NMDA受体亚型的分类和描述。 鉴定不同的受体亚群不是必要的 不仅是为了了解NMDA受体的作用，而且也是 与NMDA受体介导的癫痫发作的一般区域的基本相关性 活性和神经毒性。仅使用子类型和它们的 区分属性，有可能确定它们的相对 对正常和异常大脑功能的各个方面的贡献 开发亚型特异性拮抗剂，最大限度地保护而不是 干扰正常功能。

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.