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.

该项目将描述腺苷基环壳体（ADCY）在调节gq介导的非传统作用