Cell-specific Modulation of Feeding Behavior by Serotonin 2C Receptor RNA Processing

5-羟色胺 2C 受体 RNA 加工对摄食行为的细胞特异性调节

基本信息

批准号：
10438652
负责人：
Ronald B. Emeson
金额：
$ 38.76万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-22 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10438652
关键词：
Ablation Adenosine Adult Alternative Splicing Amino Acids Animal Model Animals Anti-Obesity Agents Appetite Depressants Behavior Behavior Disorders Biological Models Body Composition Brain Brain region Cations Cell Separation Cell physiology Cells Characteristics Chromosome 15 Complement Coupling Data Desire for food Development Diagnosis Diet Disease Eating Endoplasmic Reticulum Engineering Etiology Event Exhibits Exons Failure to Thrive Feeding behaviors G-Protein-Coupled Receptors GTP-Binding Proteins Gene Cluster Gene Expression Profiling Genetic Transcription Glucose Health Heterodimerization Homeostasis Human Hyperphagia Hypothalamic structure Inosine Insulin Knockout Mice Length Mediating Melanocortin 4 Receptor Melanocyte stimulating hormone Mental disorders Metabolic Metabolism Methods Molecular Motor Activity Mus Muscle hypotonia Mutant Strains Mice Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Oligonucleotides Pathogenesis Pathology Pathway interactions Patients Pattern Pharmacology Phenotype Physiological Population Prader-Willi Syndrome Pro-Opiomelanocortin Production Protein Isoforms RNA RNA Editing RNA I RNA Processing RNA Splicing Receptor Signaling Regulation Research Role Satiation Serotonin Receptor 5-HT2C Serum Signal Transduction Small Nucleolar RNA Structure of nucleus infundibularis hypothalami Surface Testing Therapeutic Transcript Transmembrane Domain Weaning cell type combinatorial comorbidity diet and exercise experimental study extracellular feeding food consumption in vivo insight maternal imprint member metabolic rate mouse model mutant mutant mouse model novel paraventricular nucleus receptor receptor expression receptor function reduced food intake response serotonin receptor

项目摘要

The 2C-subtype of serotonin receptor (5HT2C) has been implicated in numerous human psychiatric and behavioral disorders. The best-characterized function for this receptor however, involves an anorectic response mediated by 5HT2C receptor expression in pro-opiomelanocortin (POMC)-producing neurons in the arcuate nucleus of the hypothalamus to modulate feeding behavior and energy homeostasis. Transcripts encoding the 5HT2C receptor can be modified differentially by RNA processing events that include alternative splicing and adenosine- to-inosine (A-to-I) editing. 5HT2C transcripts can undergo up to five A-to-I editing events to generate as many as 24 protein isoforms that differ in G-protein coupling efficacy and constitutive activity, while alternative splicing can produce a truncated version of the receptor (5HT2C-tr) which decreases receptor signaling by heterodimerization and sequestration of the full-length receptor within the endoplasmic reticulum. Thus, the processing of 5HT2C RNAs may represent a critical regulatory mechanism by which neurons can modulate their responsiveness to changing extracellular signals by altering the identity of functionally distinct 5HT2C isoforms expressed in specific neuronal cell types. Unfortunately, heterogeneous expression in many brain regions and within different neuronal populations has hampered efforts to understand how 5HT2C RNA processing contributes to the modulation of specific circuits or behaviors. The long-term objectives of the proposed research are to define the cellular mechanisms that regulate 5HT2C expression and signaling, as well as possible relationships between 5HT2C processing and feeding-related pathologies. Recent studies have identified alterations in both 5HT2C receptor expression and 5HT2C-mediated behaviors in mouse models and patients diagnosed with Prader-Willi Syndrome (PWS). Furthermore, mutant mice engineered solely to express the fully edited 5HT2C receptor isoform exhibit phenotypic characteristics of PWS including a failure to thrive and post-weaning hyperphagia. Thus, RNA editing and splicing have dramatic consequences on feeding behavior suggesting that improper processing of 5HT2C transcripts may represent a contributing factor to disorders of feeding and metabolism. In the current application, mutant mouse lines in which expression of the 5HT2C-tr can be induced in POMC neurons will be characterized to assess the functional importance of 5HT2C-tr modulation for 5HT2C signaling in vivo. To assess whether manipulation of 5HT2C RNA processing represents a physiological mechanism by which neuron-dependent feeding signals are modulated, three distinct model systems will be used to examine the effects of diet, exercise and pharmacologic manipulation on 5HT2C RNA processing in POMC neurons. Finally, we will test the ability of specific, edited isoforms of the 5HT2C receptor to rescue the hyperphagia, maturity-onset obesity and type II diabetes associated with the 5HT2C-null phenotype when inducibly expressed solely in POMC neurons. It is anticipated that the proposed studies will provide critical insights into molecular etiology of human disorders associated with alterations in feeding and energy homeostasis.

5-羟色胺受体（5HT2C）的2C-亚型与许多人类的精神病和行为障碍有关。然而，该受体的最佳特征功能涉及在促蛋白素皮质（POMC）中由5HT2C受体表达介导的厌食症反应 - 在弧形核中产生神经元下丘脑调节喂养行为和能量稳态。编码5HT2C的成绩单可以通过包括替代剪接和腺苷 - 到肌苷（a-to-i）编辑。 5HT2C成绩单最多可以进行五个A到I编辑事件，以生成尽可能多的 24 G蛋白偶联功效和本构活性不同的蛋白质同工型，而替代剪接可以产生受体（5HT2C-TR）的截短版本，该版本通过异二聚体和内质网中全长受体的隔离来降低受体信号传导。因此，处理 5HT2C RNA可能代表一种关键的调节机制，通过改变其功能上不同的5HT2C同工型的身份，神经元可以通过该机制调节其对改变细胞外信号的反应。特定的神经元细胞类型。不幸的是，许多大脑区域和内部的异质表达不同的神经元种群阻碍了5HT2C RNA处理如何促进特定电路或行为的调节。拟议研究的长期目标定义调节5HT2C表达和信号传导的细胞机制，以及5HT2C处理与喂养相关病理之间的可能关系。最近的研究确定了在小鼠模型中，5HT2C受体表达和5HT2C介导的行为均和被诊断为患有的患者 Prader-Willi综合征（PWS）。此外，突变小鼠仅设计以表达完全编辑的5HT2C 受体同工型表现出PW的表型特征，包括未能繁殖和断奶后的脾气。因此，RNA编辑和剪接对喂养行为产生了巨大的后果，这表明5HT2C转录本的处理不当可能代表了喂养和代谢疾病的促成因素。在当前的应用中，可以在POMC中诱导5HT2C-TR表达的突变小鼠线神经元将被表征以评估5HT2C-TR调制在体内5HT2C信号传导的功能重要性。评估操纵5HT2C RNA处理是否代表了一种生理机制调制神经元依赖性喂养信号，将使用三个不同的模型系统来检查饮食，运动和药理操作对POMC神经元中5HT2C RNA处理的影响。最后，我们将测试5HT2C受体的特定，编辑的同工型营救成熟度 - 发作的能力肥胖和II型糖尿病与5HT2C-NULL表型相关时，仅在POMC中诱导表达神经元。预计拟议的研究将为人类分子病因提供关键的见解与喂养和能量稳态改变有关的疾病。