MOLECULAR BIOLOGY OF NEUROTRANSMITTER RECEPTORS

神经递质受体的分子生物学

• 批准号: 3860832
• 负责人: J C VENTER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3860832
• 关键词: Caenorhabditis elegans; Drosophilidae; GABA receptor; NMDA receptors; Orthoptera; Prader Willi syndrome; adrenergic receptor; benzodiazepine receptor; biochemical evolution; computer simulation; congenital nervous system disorder; genetic library; genetic mapping; genetic polymorphism; glycine receptors; human genetic material tag; human tissue; laboratory rat; molecular cloning; molecular genetics; muscarinic receptor; neurotransmitter receptor; nicotinic receptors; nucleic acid sequence; octopamine; protein sequence; protein structure function; receptor expression; serotonin receptor

This project is to characterize the gene and protein structure and evolution of neurotransmitter receptors belonging to two major multigene families. The gene families are those comprising adrenergic, muscarinic, opsin, serotonin and octopamine receptors, among others; and the second family comprising nicotinic cholinergic, GABA/benzodiazepine, NMDA, and glycine receptors. The specific aims are: to clone and sequence the genes for receptors in these two multigene families; to obtain high-density receptor expression and to use the expressed proteins to determine the complete receptor structure, in part by computer enhanced molecular modeling; to determine the evolution of the neurotransmitter receptor gene families; and to search for and characterize receptor gene polymorphisms. To date we have cloned and sequenced a significant number of receptor genes from both multigene families. These include several alpha and beta-adrenergic receptors from human and rat cDNA and genomic libraries; muscarinic cholinergic receptors from human, rat, and Drosophila genomic libraries; octopamine receptors from Drosophila; and nicotinic receptors from locusts and C. elegans. Most recently, we have cloned and sequenced the human GABA-A receptor beta- 1 and beta-3 subunits, a rat m3 muscarinic receptor genomic clone, the rat fat cell-specific (beta-3) adrenergic receptor, several C. elegans nicotinic receptor subunits, and an as yet unidentified 7-transmembrane receptor from Drosophila. In addition, more than a dozen receptor clones have been isolated in our human brain cDNA project [ZO1 NS02806-02], including the N-formylpeptide receptor, the cannabinoid receptor, and the alpha-2B-adrenergic receptor. A major finding has been the discovery that the human GABA beta-3 subunit gene lies in the locus of Prader-Willi syndrome and Angleman Syndrome on chromosome 15.

这项计划是为了表征基因和蛋白质的结构和 两个主要多基因神经递质受体的研究进展 家人。这些基因家族包括肾上腺素能、毒鼠强、 视蛋白、5-羟色胺和章鱼胺受体等；以及第二种 包括烟碱胆碱能、GABA/苯二氮卓类、NMDA和 甘氨酸受体。具体目标是：克隆和测序 这两个多基因家族中受体的基因；获得 高密度受体的表达，并利用表达的蛋白 确定完整的受体结构，部分通过计算机增强 分子模拟；以确定神经递质的进化 受体基因家族；寻找和鉴定受体基因 多态现象。到目前为止，我们已经克隆并测序了大量的 来自两个多基因家族的受体基因。其中包括几个 人和大鼠c DNA和基因组中的α和β肾上腺素能受体 文库；来自人、大鼠和 果蝇基因组文库；果蝇的章鱼胺受体；以及 蝗虫和线虫的烟碱受体。最近，我们有 人GABA-A受体β-1和β-3的克隆和序列分析 亚基，一个大鼠M3受体基因组克隆，大鼠脂肪 细胞特异性(β-3)肾上腺素能受体，几种线虫烟碱 受体亚基，以及一种尚未确定的7-跨膜受体 来自果蝇。此外，十多个受体克隆已经 在我们的人脑cDNA计划[ZO1 NS02806-02]中分离到了一个基因，包括 N-甲酰肽受体、大麻素受体和 α-2B-肾上腺素能受体。一项重大发现就是这一发现 人类GABAβ-3亚单位基因位于Prader-Willi基因座 15号染色体上的综合征和安格尔曼综合征。