Identification of 3-iodothyronamine-induced signaling network in neuromodulation

神经调节中 3-碘甲腺胺诱导的信号网络的鉴定

• 批准号: 221145281
• 负责人: Professorin Dr. Heike Biebermann
• 金额: --
• 依托单位: Institut für Experimentelle Endokrinologie (CVK)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/221145281?language=en
• 关键词: Identification; iodothyronamine; induced; signaling; network

3-iodothyronamine (3-T1AM) is a decarboxylated and deiodinated thyroid hormone metabolite. Application of 3-T1AM in mice results in a variety of effects including reduction of body temperature. Such effects qualify 3-T1AM as a potential drug for treatment of diseases such as stroke. 3-T1AM is presumed to function via activation of a G protein coupled receptor (GPCR), the trace amine associated receptor 1 (TAAR1). Recently, the existence of additional 3-T1AM targets has emerged. During the last funding period, we demonstrated that 3-T1AM also targets other GPCRs with functional effects such as the trace amine associated receptor 5 (TAAR5), the alpha 2A adrenergic receptor (ADRA2A) and the beta 2 adrenegic receptor (ADRB2).The human TAAR5 was demonstrated to have a high basal activity for Gq/11 activation and binding of 3-T1AM to TAAR5 reduces concentration-dependently the basal activity, thus functioning as an inverse agonist. In addition, ADRA2A is activated by 3-T1AM inducing Gi/o signaling. Interestingly, 3-T1AM is a biased ligand at ADR2A because in comparison to the endogenous ligand norepinephrine, 3-T1AM does not activate MAP kinase signalling. In pancreatic beta cells, ADRA2A and TAAR1 are co-expressed and both receptors play a role in glucose homeostasis. We were able to demonstrate that both receptors hetero-oligomerize. The interaction of ADR2A and TAAR1 results in the uncoupling of ADR2A from its signal transduction pathway. In addition, 3-T1AM modulates the function of beta adrenergic receptors by directly influencing isoproterenol-induced ADRB2 signaling. Most strikingly, 3-T1AM also influences the functioning of transient receptor potential channels. In the applied funding period, we aim to proceed with unravelling the targets of 3-T1AM and their functional relevance in neuromodulation by two strategies: i) Analyzing additional GPCR targets. Here, we will focus on the histamine 1 receptor (H1R), the serotonin 1B receptor (5-HTR1B) and the dopamine 2 receptor (D2R) that are involved in neuromodulation by testing the functional effects of 3-T1AM. We and others have previously demonstrated that TAAR1 and D2R and 5-HTR1B hetero-oligomerize. The functional impact of these protein-protein interactions will be investigated.ii) A newly developed method, the phosphorylated ribosome capture, will be applied which allows the isolation of only 3-T1AM activated neurons, and in turn, the determination of the RNA signature due to the application of 3-T1AM. Using this method, we aim to identify the functional outcome due to 3-T1AM activation in neurons. All identified targets will then be further investigated in order to understand 3-T1AM-induced effects following their application in mice. Here, we will initially focus on 3-T1AM-induced mechanisms in the hypothalamus. By this comprehensive approach, we aim to achieve a more thorough understanding of the role of 3-T1AM in neuromodulation and its potential therapeutic application.

3-碘甲状腺胺（3-T1AM）是一种脱羧和去碘的甲状腺激素代谢物。在小鼠体内应用3-T1AM可产生包括降低体温在内的多种效果。这样的效果使3-T1AM有资格成为治疗中风等疾病的潜在药物。据推测，3-T1AM通过激活G蛋白偶联受体（GPCR），即微量胺相关受体1 （TAAR1）发挥作用。最近，出现了额外的3-T1AM靶标。在上一个资助期内，我们证明了3-T1AM也靶向其他具有功能作用的GPCRs，如微量胺相关受体5 （TAAR5）、α 2A肾上腺素能受体（ADRA2A）和β 2肾上腺素受体（ADRB2）。人类TAAR5具有较高的Gq/11激活基础活性，并且3-T1AM与TAAR5的结合降低了基础活性的浓度依赖性，因此具有逆激动剂的作用。此外，ADRA2A被3-T1AM激活，诱导Gi/o信号转导。有趣的是，3-T1AM是ADR2A的偏配体，因为与内源性配体去甲肾上腺素相比，3-T1AM不激活MAP激酶信号传导。在胰腺β细胞中，ADRA2A和TAAR1共表达，这两种受体都在葡萄糖稳态中发挥作用。我们能够证明这两个受体都是异寡聚的。ADR2A和TAAR1的相互作用导致ADR2A从其信号转导途径中解耦。此外，3-T1AM通过直接影响异丙肾上腺素诱导的ADRB2信号传导调节β肾上腺素能受体的功能。最引人注目的是，3-T1AM还影响瞬时受体电位通道的功能。在申请资助期内，我们的目标是通过两种策略继续揭示3-T1AM的靶点及其在神经调节中的功能相关性：i)分析其他GPCR靶点。在这里，我们将重点关注组胺1受体（H1R）， 5-羟色胺1B受体（5-HTR1B）和多巴胺2受体（D2R），通过测试3-T1AM的功能影响参与神经调节。我们和其他人之前已经证明TAAR1、D2R和5-HTR1B是异寡聚的。这些蛋白质-蛋白质相互作用的功能影响将被研究。ii)一种新开发的方法，磷酸化核糖体捕获，将被应用，它允许仅分离3-T1AM激活的神经元，进而确定由于3-T1AM的应用而产生的RNA特征。使用这种方法，我们的目标是确定神经元中3-T1AM激活的功能结果。所有确定的靶点将进一步研究，以了解3- t1am在小鼠中应用后的诱导效应。在这里，我们将首先关注3- t1am在下丘脑中的诱导机制。通过这种全面的方法，我们旨在更全面地了解3-T1AM在神经调节中的作用及其潜在的治疗应用。