Post-transcriptional Regulation of Serotonin Receptors

血清素受体的转录后调节

• 批准号: 7010646
• 负责人: Ronald B. Emeson
• 金额: $ 33.91万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7010646
• 关键词: 3T3 cells; G protein; biological signal transduction; cell population study; cell transformation; cytoskeleton; embryonic stem cell; fibroblasts; gene targeting; genetic regulation; genetically modified animals; high throughput technology; intermolecular interaction; laboratory mouse; mitogen activated protein kinase; molecular site; phospholipase C; phospholipase D; posttranscriptional RNA processing; protein isoforms; protein structure function; receptor expression; serotonin; serotonin receptor

DESCRIPTION (provided by applicant): Serotonin (5-hydroxytryptamine; 5-HT) is a monoaminergic neurotransmitter that modulates numerous sensory and motor processes as well as a wide variety of behaviors including sleep, appetite, pain perception, locomotion, thermoregulation, hallucinations, and sexual behavior. Recent studies from our laboratory have indicated that the function of the 2C-subtype of serotonin receptor (5-HT2 c R) is modulated by a novel RNA modification process referred to as RNA editing. Editing of 5-HL2cR transcripts is responsible for the tissue-specific expression of as many as twenty-four 5-HT2cR isoforms and is proposed to represent a regulatory mechanism by which cells modulate their response to extracellular signals by altering the efficacy and specificity of receptor/G-protein interactions; the long term objectives of the proposed research are to define the cellular mechanisms involved in the regulation of serotonergic signal transduction in the central nervous system. We propose to examine the signaling properties of distinct 5-HT2cR isoforms using a high-throughput, cell-based assay to identify functional interactions between 5-HT, cR isoforms and the a-subunits of several heterotrimeric G-proteins. These studies will be extended to examine the functional responses of other edited 5-HT2cR isoforms that are highly expressed in the rat and human brain and to dissect the 5-HT2cR-activated signaling pathways leading to activation of phospholipase D, mitogenactivated (MAP) kinase and rearrangements of the actin cytoskeleton. To examine the physiological relevance of multiple, edited 5-HT2cR isoforms, mice capable of expressing only, a single 5-HT2CR isoform will be generated by targeted gene modification in embryonic stem cells; the non-edited (INI) and fully-edited (VGV) 5-HT2c R isoforms have been selected for these studies, as they demonstrate the greatest differences in receptor: G-protein coupling efficacy In additional to gross alterations in animal phenotype and brain morphology, mutant mice will be examined for alterations in physiological systems in which the 5-HT2cR has already been implicated, including tumorigenesis, seizure activity, feeding behavior, locomotor activity and hippocampal function. To further examine the role of 5-HT2cR editing in cellular transformation, NIH-3T3 cells expressing specific 5-HT2cR isoforms will be assessed for a number of transformed cellular characteristics including increased mitogenesis, loss of contact inhibition, loss of anchorage dependence and the ability to generate tumors in nude mice. It is anticipated that these studies will provide new insights concerning the regulation of cellular processes involved in the transduction of serotonergic signals and the role(s) of multiple serotonin receptors in the nervous system.

描述（由申请人提供）： 血清素（5-羟色胺；5-HT）是一种 调节多种感觉和运动的单胺能神经递质 过程以及各种行为，包括睡眠、食欲、 疼痛知觉、运动、体温调节、幻觉和性 行为。我们实验室最近的研究表明，该功能 5-羟色胺受体 (5-HT2 c R) 的 2C 亚型由一种新型 RNA 调节 修饰过程称为RNA编辑。 5-HL2cR 转录本的编辑 负责多达二十四个的组织特异性表达 5-HT2cR 亚型并被提议代表一种调节机制，通过该机制 细胞通过改变功效来调节其对细胞外信号的反应 和受体/G蛋白相互作用的特异性；的长期目标 拟议的研究旨在定义参与的细胞机制 中枢神经系统血清素信号转导的调节。 我们建议检查不同 5-HT2cR 亚型的信号传导特性 使用高通量、基于细胞的测定来识别功能相互作用 5-HT、cR 同工型和几个异源三聚体的 a 亚基之间 G-蛋白。这些研究将扩展到检查功能反应 在大鼠和人类中高度表达的其他编辑的 5-HT2cR 亚型 大脑并剖析 5-HT2cR 激活的信号通路导致 磷脂酶 D、丝裂原激活 (MAP) 激酶的激活和重排 肌动蛋白细胞骨架。 为了检查多个经过编辑的 5-HT2cR 亚型的生理相关性， 只能够表达单一5-HT2CR亚型的小鼠将通过以下方式产生 胚胎干细胞的靶向基因修饰；未编辑的 (INI) 和 这些研究已选择完全编辑 (VGV) 5-HT2c R 同工型，如 它们表现出最大的差异在于受体：G蛋白偶联 功效 除了动物表型和大脑的总体改变之外 形态学方面，将检查突变小鼠的生理变化 5-HT2cR 已经涉及的系统，包括 肿瘤发生、癫痫发作活动、进食行为、运动活动和 海马体功能。 为了进一步研究 5-HT2cR 编辑在细胞转化中的作用， 将评估表达特定 5-HT2cR 同工型的 NIH-3T3 细胞 一些转化的细胞特征，包括增加有丝分裂， 失去接触抑制、失去锚定依赖性和能力 在裸鼠体内产生肿瘤。预计这些研究将提供 关于参与细胞过程调节的新见解 血清素信号的转导和多种血清素的作用 神经系统中的受体。

项目成果

Mouse models to elucidate the functional roles of adenosine-to-inosine editing.

小鼠模型阐明腺苷至肌苷编辑的功能作用。

• DOI: 10.1016/s0076-6879(07)24016-9
• 发表时间: 2007
• 期刊: Methods in enzymology
• 作者: Rula,ElizabethY;Emeson,RonaldB
• 通讯作者: Emeson,RonaldB

RNA editing of the human serotonin 5-HT(2C) receptor delays agonist-stimulated calcium release.

人类血清素 5-HT(2C) 受体的 RNA 编辑可延迟激动剂刺激的钙释放。

• DOI: 10.1124/mol.58.4.859
• 发表时间: 2000
• 期刊: Molecular pharmacology
• 影响因子: 3.6
• 作者: Price,RD;Sanders-Bush,E
• 通讯作者: Sanders-Bush,E