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

本项目将描述腺苷酸环化酶（ADCY）在调节Gq介导的细胞凋亡中的非传统作用。 信号和突触长期抑制LTD（LTD）在正常脑和病理生理学相关 脆性X综合征（FXS）。G蛋白偶联受体的特定基团的激活刺激Gq，并且在 turn触发信号转导级联，导致突触可塑性依赖性，如LTD。 与神经系统疾病、Gq偶联代谢型谷氨酸受体5（mGluR 5）功能亢进相关 和毒蕈碱型乙酰胆碱受体（Gq-mAchR）以及翻译水平的升高是导致 FXS中的神经元功能障碍。我们最近发现，1型腺苷酸环化酶（ADCY 1）水平异常， 在FXS小鼠模型（即Fmr 1敲除小鼠）中增加。基因缺失或药理学抑制 ADCY 1纠正核心细胞和行为症状。有趣的是，与目前的 对Gq的理解，其中不考虑ADCY和cAMP介导的信号传导的功能， 我们发现ADCY 1是mGluR 5激活后LTD所必需的。根据这些结果，我们 中心假设是，Ca 2+刺激的ADCY 1是Gq信号传导的功能组分，从而 FXS中ADCY 1表达的异常升高解释了Gq介导的突触增强， 功能障碍和异常升高的翻译。该项目将首先解决ADCY 1如何调节Gq 正常神经元中的信号传导、翻译和Gq-LTD。其次，它将解决ADCY 1升高如何控制 不同翻译过程的改变，以及ADCY 1升高是否是Gq介导的突触 FXS神经元功能障碍。考虑到传统观点强调PLC的作用 （磷脂酶C）-Ca 2 +/PKC（蛋白激酶C）级联而不是Gq信号中的ADCY/cAMP，验证 ADCY 1在Gq介导的信号传导和Gq-LTD中的功能将表明实质性的范式转变/修饰 并重新定义Gq在神经元中的功能。该项目的结果还将提供新的见解， FXS的病理生理和发病机制。ADCY 1作为FMRP（Fragile X 精神发育迟滞蛋白），将改变的Gq信号级联与异常翻译和突触 FXS功能障碍。它将揭示一个新的概念，即异常ADCY 1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， 效率，从而促进我们对FXS病理学的理解。考虑到ADCY 1仅为 在中枢神经系统中表达，并在功能上与多种信号分子连接， 改变FXS，结果也将表明一个有吸引力的和机制为基础的治疗。

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.