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

ADCY 在 Gq 介导的神经元信号传导和神经可塑性中的非常规作用

• 批准号: 9900871
• 负责人: Hongbing Wang
• 金额: $ 44.74万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900871
• 关键词: Ablation; Address; Adenylate Cyclase; Affect; Attenuated; Behavioral Symptoms; Brain; Cell physiology; Coupled; Cyclic AMP; Data; Disease; Epilepsy; FMR1; FMRP; Fragile X Syndrome; Functional disorder; G-Protein-Coupled Receptors; Genetic; Intellectual functioning disability; Knockout Mice; Link; Long-Term Depression; MAPK3 gene; Mediating; Modification; Molecular Target; Mus; Muscarinic Acetylcholine Receptor; Mutation; Neuraxis; Neuronal Dysfunction; Neuronal Plasticity; Neurons; Pathologic; Pathology; Pharmacology; Phospholipase C; Physiological; Play; Protein Biosynthesis; Protein Kinase C; Receptor Activation; Role; Signal Transduction; Signaling Molecule; Synapses; Synaptic plasticity; Therapeutic; Transgenic Organisms; Translation Process; Translations; Up-Regulation; Validation; adenylyl cyclase 1; autism spectrum disorder; base; insight; metabotropic glutamate receptor 5; mouse model; nervous system disorder; neurotransmission; novel; optogenetics; receptor; relating to nervous system; response; synaptic function; theories

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.

该项目将描述adenylyl圆圈（ADCY）在调节GQ介导的中的非规定作用 正常脑和病理生理学的信号传导和突触长期抑郁有限公司（LTD）与 脆弱的X综合征（FXS）。特定的G蛋白偶联受体的激活刺激GQ，在 转向触发信号转导级联，导致依赖翻译的突触可塑性，例如Ltd。 与神经系统疾病有关，GQ耦合的代谢型谷氨酸受体5（MGLUR5）的超功能 和毒蕈碱乙酰胆碱受体（GQ-MACHR）以及升高的翻译基于多个方面 FXS中的神经元功能障碍。我们最近发现，1型adenylyl圆柱体（ADCY1）水平异常为 FXS小鼠模型（即FMR1基因敲除小鼠）的增加。遗传缺失或药理学抑制 ADCY1纠正核心细胞和行为症状。有趣的是，与电流不一致 对GQ的理解，其中不考虑ADCY和CAMP介导的信号的功能， 我们发现MGLUR5激活后ADCY1对于LTD至关重要。基于这些结果，我们 中心假设是Ca2+刺激的ADCY1是GQ信号的功能组成部分，从而 FXS中异常升高的ADCY1表达是夸张的GQ介导的突触 功能障碍和异常升高的翻译。该项目将首先解决ADCY1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ADCY1高架的管理 不同的翻译过程的改变，以及升高的ADCY1是否是GQ介导的突触的因果 FXS神经元功能障碍。考虑到传统观点强调了PLC的作用 （磷脂酶C）-ca2+/pkc（蛋白激酶C）级联而不是GQ信号中的adcy/CAMP，验证 GQ介导的信号传导和GQ-LTD中的ADCY1函数将表明大量范式偏移/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新的见解 FXS中的病理生理和疾病机制。它将揭示ADCY1作为FMRP的关键目标（脆弱的X 智力低下 FXS中的功能障碍。它将发现一个新概念，异常ADCY1介导的信号导致 通过翻译过程的不同方面（例如翻译能力和）改变了全球翻译 效率，从而提高我们对FXS病理学的理解。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 随着FXS的改变，结果还将提出一种有吸引力的基于机制的治疗。