Identification of 3-iodothyronamine-induced signaling network in neuromodulation

点击翻译按钮获取中文摘要

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.