Identification of ligands that bind to the orphan delta2 receptor

鉴定与孤儿 delta2 受体结合的配体

基本信息

批准号：
7588965
负责人：
Stephen F Traynelis
金额：
$ 20.34万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7588965
关键词：
AMPA Receptors Agonist Allosteric Regulation Amino Acids Binding Bioinformatics Brain Cell model Cells Cerebellum Chemicals Chromosome Pairing Class Cleaved cell Closure Complex Computer Simulation Crystallography Data Databases Development Evaluation Family Genes Glutamate Receptor Glutamates Glycine Goals Ion Channel Lead Learning Ligand Binding Ligand Binding Domain Ligands Manufacturer Name Mediating Memory Modeling Molecular Molecular Conformation Motor Mus Mutation NR1 gene Neurons Nucleic Acid Sequence Homology Orphan Paper Pharmacology Phenotype Play Point Mutation Property Proteins Public Health Range Recombinants Regulation Research Role Serine Signal Transduction Site Structure Synapses Synaptic Transmission Synaptic plasticity Testing Therapeutic Agents Thinking Time Tissues Vacuum Xenopus oocyte desensitization glutamate receptor delta 2 human NR1 protein in vivo inhibitor/antagonist insight kynurenate mutant neuropathology novel novel therapeutics receptor receptor function receptor structure function research study response scaffold tool trafficking virtual

项目摘要

DESCRIPTION (provided by applicant): The glutamate receptor family is comprised of 18 genes that can combine to form dozens of different heteromeric receptor complexes. This receptor class mediates most excitatory synaptic transmission in the mammalian brain, and plays a central role in cellular models of learning and memory as well as a wide range of neuropathologies. Of these gene products, two orphan receptor subunits (delta1 and delta2) have been designated to be in the glutamate receptor family on the basis of sequence homology even though no activating ligand has been identified. The delta2 subunit is expressed at cerebellar synapses, and a variety of electrophysiological studies suggest that delta2 plays an important role in cerebellar development and synaptic plasticity. In addition, mice that either lack the delta2 subunit or express a constitutively active mutant form of this receptor (delta2-lurcher), show distinct phenotypes with motor disturbances. Thus, a paradox exists whereby the delta2 glutamate receptor subunit is thought to play an important role in brain function yet there is a vacuum regarding what we know about the receptor. Our collaborators have recently used crystallography to determine that a small amino acid (D-serine) can bind to the delta2 ligand binding domain, making a set of atomic contacts that are consistent with glutamate binding at other glutamate receptor subunits. Interestingly, although D-serine binds to the delta2 subunit, it does not induce any current response in wild- type receptors. However, a naturally occurring point mutation within the delta2 subunit (the lurcher mutation) produces constitutively active homomeric channels, and application of D- serine to these channels inhibits the tonic current flowing through these constitutively active channels. These data suggest that binding of D-serine can lead to changes in gating, and raises the possibility that incorporation of the delta2 subunit into heteromeric receptor assemblies may endow glutamate receptors with a regulatory site for D-serine. These new data provide an unprecedented opportunity to explore delta2 receptor structure, function, and pharmacology. We propose to exploit this recent finding in 2 lines of experimentation: Aim 1: Identify new ligands that potently activate or inhibit delta2 receptors. Aim 2: Evaluate whether co-expression of delta2 with other glutamate receptor subunits adds D-serine sensitivity to the receptors. Completion of these studies will provide the first comprehensive pharmacological evaluation of this receptor class, as well as new tools with which to study its function and regulation in brain. PUBLIC HEALTH RELEVANCE: Our recent findings that D-serine can bind to the orphan glutamate receptor delta2 has provided an opportunity to significantly advance our understanding of the function of this receptor, which has been enigmatic for over a decade despite in vivo findings that suggest an important role in cerebellar development and synaptic plasticity. The goal of these studies is to identify novel and selective pharmacological agents (activators and antagonists) that could be useful research tools for understanding delta2 function in tissue. In addition, we will also test whether delta2 subunit alters the effects of D-serine on hetero-mulitmeric glutamate receptors. Completion of these studies will advance our understanding of delta2 function, which holds implications for neuronal signaling, synaptic plasticity, and neuronal development in the cerebellum. These studies may also provide insight into new therapeutic agents that target the delta2 receptor.

描述（由申请人提供）：谷氨酸受体家族由18个基因组成，这些基因可以结合形成数十个不同的杂体受体复合物。该受体类介导哺乳动物大脑中最兴奋的突触传播，并在学习和记忆的细胞模型以及广泛的神经病理学中起着核心作用。在这些基因产物中，即使未鉴定出尚未鉴定出激活的配体，但已指定为谷氨酸受体家族中的两个孤儿受体亚基（Delta1和delta2）。 Delta2亚基在小脑突触上表达，各种电生理研究表明，Delta2在小脑发育和突触可塑性中起重要作用。此外，要么缺乏Delta2亚基或表达该受体（Delta2-Lurcher）组成型活性突变体形式的小鼠显示出具有运动障碍的不同表型。因此，存在一个悖论，在这种悖论中，Delta2谷氨酸受体亚基被认为在大脑功能中起着重要作用，但关于我们对受体的了解有真空。我们的合作者最近使用晶体学来确定一个小氨基酸（D-丝氨酸）可以与Delta2配体结合结构域结合，从而使一组与其他谷氨酸受体亚基处的谷氨酸结合一致的原子接触。有趣的是，尽管D-丝氨酸与Delta2亚基结合，但它不会引起野生型受体的任何当前反应。然而，Delta2亚基（Lurcher突变）内的天然发生的点突变会产生组成性活跃的同源通道，并且D-丝氨酸在这些通道中的应用抑制了通过这些强度活性通道流过的强直电流。这些数据表明，D丝氨酸的结合可以导致门控的变化，并提高了将Delta2亚基掺入异源受体组件中的可能性可能会使谷氨酸受体赋予D-次氨酸的调节位点。这些新数据为探索Delta2受体结构，功能和药理学提供了前所未有的机会。我们建议在两行实验中利用这一发现：目标1：确定有效激活或抑制Delta2受体的新配体。 AIM 2：评估Delta2与其他谷氨酸受体亚基的共表达是否对受体增加了D-丝氨酸敏感性。这些研究的完成将为该受体类别提供首次全面的药理学评估，以及研究其在大脑中功能和调节的新工具。公共卫生相关性：我们最近的发现，D丝氨酸可以与谷氨酸受体Delta2结合结合，这为我们提供了一个机会，可以显着促进我们对该受体功能的理解，尽管体内发现在小脑发育和突触可塑性中表明了重要的作用，但它已经有十多年了。这些研究的目的是识别新型和选择性的药理学剂（激活剂和拮抗剂），这些药理学剂（激活剂和拮抗剂）可能是理解组织中Delta2功能的有用研究工具。此外，我们还将测试Delta2亚基是否会改变D-丝氨酸对杂氨酸谷氨酸受体的影响。这些研究的完成将提高我们对Delta2功能的理解，这对小脑的神经元信号传导，突触可塑性和神经元发育有影响。这些研究还可以提供对靶向Delta2受体的新治疗剂的见解。