Nonconventional role of ADCY in Gq-mediated neuronal signaling and neuroplasticity

这个项目将描述腺苷环状蛋白(ADCY)在调节GQ介导的过程中的非常规作用 正常脑内信号和突触长时程增强抑制及其相关的病理生理机制 脆性X综合征(FXS)。激活特定的G蛋白偶联受体组刺激GQ，并在 TURN触发信号转导级联反应，导致翻译依赖性突触可塑性，如LTD。 Gq偶联代谢型谷氨酸受体5(MGluR5)功能亢进与神经功能障碍 和M胆碱型乙酰胆碱受体(GQ-mAchR)以及翻译水平的提高是多方面的基础 FXS中的神经元功能障碍。我们最近发现，1型腺苷酸环状病毒(ADCY1)水平异常 在FXS小鼠模型(即Fmr1基因敲除小鼠)中增加。基因缺失或药物抑制 ADCY1可纠正核心细胞和行为症状。耐人寻味的是，与当前的 对GQ的理解，其中没有考虑ADCY和cAMP介导的信号转导功能， 我们发现ADCY1在mGluR5激活后对LTD是必不可少的。基于这些结果，我们的 中心假设是，钙离子刺激的ADCY1是GQ信号的一个功能成分，因此 FXS中ADCY1的异常高表达是GQ介导突触过度的原因 功能障碍和异常升高的翻译。这个项目将首先解决ADCY1是如何调节GQ的 正常神经元中的信号、翻译和GQ-LTD。其次，它将解决提升的ADCY1如何管理 不同翻译过程中的变化以及ADCY1升高是否是GQ介导的突触的原因 FXS神经元功能障碍。考虑到传统观点强调PLC的作用 在GQ信号中，(磷脂酶C)-钙/蛋白激酶C(PKC)级联而不是ADCY/cAMP，验证 ADCY1在GQ介导的信号转导和GQ-LTD中的功能将导致实质性的范式转变/修改 并重新定义GQ在神经元中的功能。该项目的结果还将提供对 FXS的病理生理和发病机制。它将揭示ADCY1，作为FMRP(脆性X)的关键靶标 智力低下蛋白)，将改变的GQ信号级联与异常翻译和突触联系起来 FXS功能障碍。它将揭示一个新的概念，即异常的ADCY1介导的信号转导有助于 通过翻译过程的不同方面改变全球翻译，如翻译能力和 效率，从而增进我们对FXS病理的理解。考虑到ADCY1只是 在中枢神经系统中表达，并在功能上连接到多个信号分子，这些分子 在FXS中进行改变，结果也将表明一种有吸引力的基于机制的疗法。

This project will delineate a non-conventional role of adenylyl cylcase (ADCY) in regulating Gq-mediated signaling and synaptic long-term depression LTD (LTD) in normal brain and pathophysiology associated with Fragile X syndrome (FXS). Activation of specific groups of G protein-coupled receptors stimulates Gq, and in turn triggers signal transduction cascade, leading to translation-dependent synaptic plasticity such as LTD. Relevant to neurological disorders, hyper-function of Gq-coupled metabotropic glutamate receptor 5 (mGluR5) and muscarinic acetylcholine receptor (Gq-mAchR) as well as elevated translation underlie multiple aspects of neuronal dysfunction in FXS. We recently found that type 1 adenylyl cylcase (ADCY1) level is aberrantly increased in FXS mouse model (i.e. Fmr1 knockout mice). Genetic deletion or pharmacological inhibition of ADCY1 corrects core cellular and behavioral symptoms. Intriguingly, inconsistent with the current understanding on Gq, of which the functions of ADCY and cAMP-mediated signaling are not considered, we found that ADCY1 is essential for LTD following activation of mGluR5. Based on these results, our central hypothesis is that the Ca2+-stimulated ADCY1 is a functional component of Gq signaling, and thereby the abnormally elevated ADCY1 expression in FXS accounts for the exaggerated Gq-mediated synaptic dysfunction and aberrantly elevated translation. This project will first address how ADCY1 regulates Gq signaling, translation, and Gq-LTD in normal neurons. Second, it will address how elevated ADCY1 governs alterations in distinct translation process, and whether elevated ADCY1 is causal for Gq-mediated synaptic dysfunction in FXS neurons. Considering that the conventional view emphasizes the role of PLC (phospholipase C)-Ca2+/PKC (protein kinase C) cascade rather than ADCY/cAMP in Gq signaling, validation of ADCY1 function in Gq-mediated signaling and Gq-LTD will suggest a substantial paradigm shift/modification and re-define how Gq functions in neurons. The results of this project will also provide new insights into pathophysiology and disease mechanism in FXS. It will reveal that ADCY1, as a key target of FMRP (Fragile X mental retardation protein), connects altered Gq signaling cascades with abnormal translation and synaptic dysfunction in FXS. It will uncover a new concept that the abnormal ADCY1-mediated signaling contributes to altered global translation via distinct aspects of translation processes such as translation capacity and efficiency, and thereby advance our understanding on FXS pathology. Considering that ADCY1 is only expressed in the central nervous system and functionally connected to multiple signaling molecules that are altered in FXS, the results will also suggest an attractive and mechanism-based therapy.