Adrenergic Receptor Mechanisms in Antidepressant Therapy

肾上腺素能受体（AR）是中枢神经系统（CNS）介导的行为和几种神经功能（包括情绪、记忆、神经内分泌控制和自主功能刺激）的重要调节剂。肾上腺素能受体数量的改变与情感性精神障碍（包括抑郁症）的病理生理学有关。β-肾上腺素能受体（β-AR）下调发生在慢性治疗期间， 抗抑郁药，这表明β-肾上腺素能受体（β 1-AR）亚型（大脑中主要的β- AR亚型）的失调可能与抑郁症有关。我们建议开发抗抑郁治疗过程中的转录和转录后β 1-AR mRNA控制的机制的理解。我们已经研究了激动剂诱导后β 1-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，我们最近已经确定，RNA结合因子HuR，hnRNP A1和AUF-1都与大鼠61- AR mRNA的3'非翻译区（UTR）相互作用，并且HuR在β-AR激动剂异丙肾上腺素的存在下被诱导，导致61-AR转录物降解的加速。其次，我们已经确定，暴露于C6细胞异丙肾上腺素导致诱导型环磷酸腺苷早期阻遏物（ICER）和其他相关的CREM（环磷酸腺苷反应元件（CRE）调制器）的mRNA的快速诱导在两个小时的刺激，并用于抑制β 1-AR基因转录。第三，我们已经在β 1-AR基因中鉴定了另一个转录阻遏物区域，包括位置-396到-367，并且已经鉴定了阻遏物分子作为新的bZIP样转录因子。我们将慢性注入各种抗抑郁药到大鼠和恒河猴，并恢复皮质标本，以确定β 1-AR mRNA下调的具体分子机制。这一信息可能为肾上腺素能受体在抑郁症中的分子作用提供依据，并有助于更好地理解抗抑郁治疗的疗效。因此，这一R21赠款提交是响应PA-00-073的目标4，“初步研究和发展，以建立重要的未来研究”。具体目标1的主要实验目的是验证RNA结合蛋白HuR、hnRNP A1和/或AUF-1是参与抗抑郁药诱导的β 1-AR mRNA下调的降解分子，并确定抗抑郁药是否通过与HuR和其他选择性HuR配体的相互作用触发β 1-AR mRNA的核质输出。具体目标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β 1-AR基因表达的潜在阻遏物。

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.