Adrenergic Receptor Mechanisms in Antidepressant Therapy

抗抑郁治疗中的肾上腺素受体机制

基本信息

批准号：
6580613
负责人：
CURTIS A MACHIDA
金额：
$ 15.9万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-12-01 至 2004-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6580613
关键词：
Macaca mulatta RNA binding protein antidepressants beta adrenergic receptor clinical depression gene expression genetic regulation imipramine isoproterenol laboratory rat mental disorder chemotherapy messenger RNA pharmacokinetics psychopharmacology receptor expression transcription factor

项目摘要

Adrenergic receptors (ARs) serve as important regulators of central nervous system- (CNS-) mediated behavior and several neural functions, including mood, memory, neuroendocrine control, and stimulation of autonomic function. Alterations in adrenergic receptor number have been implicated in the pathophysiology of affective psychiatric disorders, including depression. Beta-adrenergic receptor (beta-AR) down-regulation occurs during chronic treatment with antidepressants, suggesting that the dysregulation of the betal-adrenerqic receptor (beta1-AR) subtype, the predominant beta- AR subtype in the brain, may be associated with depressive illness. We propose to develop a mechanistic understanding of transcriptional and post-transcriptional beta1-AR mRNA control during antidepressant therapy. We have examined the molecular mechanisms underlying beta1-AR mRNA down-regulation following agonist induction, and have identified potential transcriptional and post-transcriptional control mechanisms. Firstly, we have recently determined that the RNA binding factors HuR, hnRNP A1, and AUF-1 all interact with the 3' untranslated region (UTR) of the rat 61- AR mRNAs, and that HuR becomes induced in the presence of beta-AR agonist isoproterenol, resulting in the acceleration of _I-AR transcript degradation. Secondly, we have determined that exposure of C6 cells to isoproterenol results in a rapid induction of inducible cyclic AMP early repressor (ICER) and other related CREM (cyclic AMP response element (CRE) modulator) mRNA within two hours of stimulation, and serves to repress beta1-AR gene transcription. And thirdly, we have identified another transcriptional repressor region in the beta1-AR gene, encompassing positions -396 to -367, and have identified the repressor molecule as a novel bZlP-like transcription factor. We will chronically-infuse various antidepressants into rats and rhesus macaques, and recover cortical specimens to identify the specific molecular mechanisms underlying beta1-AR mRNA down-regulation. This information may provide insiahts in the molecular role of the adrenerqic receptors in depression, and develop a better understandinq of the efficacy of antidepressant treatment. Thus, this R21 grant submission is responsive to objective 4 of PA-00-073, "initial research and development for building significant future research". The primary experimental objectives of Specific Aim 1 are to verify that the RNA binding proteins HuR, hnRNP A1, and/or AUF-1 are the degradative molecules involved in antidepressant-induced beta1-AR mRNA down-regulation, and to determine whether antidepressants trigger the nucleocytoplasmic export of beta1-AR mRNAs, via interaction with HuR and other selective HuR ligands. The primary experimental objectives of Specific Aim 2 are to validate ICER and the novel bZlP-like transcription factor as potential repressors of beta1-AR gene expression during antidepressant therapy.

肾上腺素能受体 (AR) 是中枢神经系统 (CNS) 介导的行为和多种神经功能的重要调节剂，包括情绪、记忆、神经内分泌控制和自主神经功能刺激。肾上腺素能受体数量的改变与情感精神疾病（包括抑郁症）的病理生理学有关。长期治疗期间会发生β-肾上腺素能受体（β-AR）下调抗抑郁药，表明β-肾上腺素受体（β1-AR）亚型（大脑中主要的β-AR亚型）的失调可能与抑郁症有关。我们建议对抗抑郁治疗期间转录和转录后 β1-AR mRNA 控制有一个机制上的理解。我们研究了激动剂诱导后 β1-AR mRNA 下调的分子机制，并确定了潜在的转录和转录后控制机制。首先，我们最近确定 RNA 结合因子 HuR、hnRNP A1 和 AUF-1 均与大鼠 61-AR mRNA 的 3' 非翻译区 (UTR) 相互作用，并且 HuR 在存在 β- 的情况下被诱导。 AR激动剂异丙肾上腺素，导致_I-AR转录物降解加速。其次，我们已经确定，C6 细胞暴露于异丙肾上腺素会导致在刺激后两小时内快速诱导诱导型环 AMP 早期阻遏物 (ICER) 和其他相关的 CREM（环 AMP 反应元件 (CRE) 调节剂）mRNA，并有助于抑制 beta1-AR 基因转录。第三，我们在β1-AR基因中鉴定了另一个转录阻遏物区域，涵盖位置-396至-367，并且鉴定了该阻遏物分子为新型bZIP样转录因子。我们将向大鼠和恒河猴长期注射各种抗抑郁药物，并回收皮质标本，以鉴定β1-AR mRNA下调的具体分子机制。这些信息可以提供肾上腺素受体在抑郁症中的分子作用的信息，并更好地理解抗抑郁治疗的功效。因此，此次 R21 拨款申请响应了 PA-00-073 的目标 4，“为构建重要的未来研究而进行的初步研究和开发”。具体目标 1 的主要实验目标是验证 RNA 结合蛋白 HuR、hnRNP A1 和/或 AUF-1 是参与抗抑郁药诱导的 β1-AR mRNA 下调的降解分子，并确定抗抑郁药是否触发通过与 HuR 和其他选择性 HuR 配体相互作用，β1-AR mRNA 的核细胞质输出。 Specific Aim 2 的主要实验目标是验证 ICER 和新型 bZIP 样转录因子作为抗抑郁治疗期间 β1-AR 基因表达的潜在抑制剂。