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: 10082304
• 负责人: Hongbing Wang
• 金额: $ 44.65万
• 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/10082304
• 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.

该项目将描述腺苷酸环化酶 (ADCY) 在调节 Gq 介导的过程中的非常规作用 正常大脑中的信号传导和突触长期抑制LTD（LTD）及其相关的病理生理学 脆性 X 综合征 (FXS)。特定 G 蛋白偶联受体基团的激活会刺激 Gq，并在 转向触发信号转导级联，导致依赖于翻译的突触可塑性，例如 LTD。 与神经系统疾病、Gq 偶联代谢型谷氨酸受体 5 (mGluR5) 功能亢进相关 和毒蕈碱乙酰胆碱受体 (Gq-mAchR) 以及翻译升高是多个方面的基础 FXS 中的神经元功能障碍。我们最近发现 1 型腺苷酸环化酶 (ADCY1) 水平异常 FXS 小鼠模型（即 Fmr1 敲除小鼠）中增加。基因缺失或药理学抑制 ADCY1 纠正核心细胞和行为症状。奇怪的是，与现在的情况不符 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 ADCY1 对于 mGluR5 激活后的 LTD 至关重要。根据这些结果，我们 中心假设是 Ca2+ 刺激的 ADCY1 是 Gq 信号传导的功能成分，因此 FXS 中 ADCY1 表达异常升高是 Gq 介导的突触过度增加的原因 功能障碍和翻译异常升高。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 升高后如何进行控制的问题 不同翻译过程的改变，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 Gq 信号传导中的（磷脂酶 C）-Ca2+/PKC（蛋白激酶 C）级联而不是 ADCY/cAMP，验证 ADCY1 在 Gq 介导的信号传导和 Gq-LTD 中的功能将表明重大的范式转变/修改 并重新定义 Gq 在神经元中的功能。该项目的结果也将提供新的见解 FXS 的病理生理学和疾病机制。它将揭示ADCY1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联系起来 FXS 功能障碍。它将揭示一个新概念，即异常 ADCY1 介导的信号传导有助于 通过翻译过程的不同方面（例如翻译能力和 效率，从而增进我们对 FXS 病理学的理解。考虑到 ADCY1 仅 在中枢神经系统中表达并与多种信号分子功能性连接 FXS 的改变，结果也将表明一种有吸引力的、基于机制的治疗。