Phosphodiesterases govern nuclear cAMP signaling for gene expression

磷酸二酯酶控制基因表达的核 cAMP 信号传导

基本信息

批准号：
10717183
负责人：
YANG K XIANG
金额：
$ 61.77万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10717183
关键词：
A kinase anchoring protein Adrenergic Agents Adrenergic Receptor Affect Agonist Alanine Anxiety Arrestins Binding Biosensor Cell Nucleus Cell membrane Cognition Complex Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic Nucleotides Data Dementia Development Disease Dopamine Receptor Endocytosis Endosomes Family Fibroblasts Fluorescence Resonance Energy Transfer G protein coupled receptor kinase G-Protein-Coupled Receptors Gene Expression Gene Expression Regulation Genetic Hippocampus Human Impairment Ion Channel Knock-out Knockout Mice Learning Literature Mediating Memory Mental Depression Mus Muscle Cells Neurons Nuclear Nuclear Export Phosphorylation Physiological Play Post-Traumatic Stress Disorders Protein Isoforms Proteins Receptor Signaling Regulation Rodent Role Serine Shapes Signal Transduction Signaling Protein Site System Tissues Training Transgenic Mice arrestin3 beta-2 Adrenergic Receptors beta-adrenergic receptor biological adaptation to stress inhibitor morris water maze nanobodies neuronal excitability novel overexpression phosphoric diester hydrolase receptor recruit response scaffold

项目摘要

Abstract Studies have established the critical roles of a superfamily of phosphodiesterases (PDEs) in hydrolyzing cAMP and its subcellular distribution. We aim to explore the role of PDEs in differential regulation of the cAMP signals at the plasma membrane and in the nucleus. Specifically, we will uncover the regulation of the nuclear cAMP signals under the CNS β2-adrenergic receptor (b2AR) stimulation in hippocampal (HC) neurons during learning and memory. Interestingly, PDE4 inhibitors benefit learning and memory in rodents and humans, indicating that PDE4 may control the βAR-induced cAMP signal in the nucleus. PDE4D isoforms are associated with β2AR to fine-tune subcellular cAMP-PKA signals in fibroblasts and myocytes, and PDE4D5 is associated with an AKAP95/PKA complex in the nucleus. Our preliminary data show that βAR stimulation promotes the nuclear export of PDE4D5 in HC neurons. This relocation of PDE4D5 depends on endosome GRK-phosphorylated b2AR and is critically necessary for delivering cAMP signals into the nucleus. Besides the GRK-phosphorylated b2AR, we have recently characterized another distinct subpopulation of b2AR that are PKA-phosphorylated and located at the PM after agonist stimulation in HC neurons. We hypothesize that two b2AR subpopulations synergistically promote nuclear cAMP signal by arrestin3-dependent export of PDE4D5 from the nucleus. We will characterize the mechanisms underlying the PDE4D5-dependent regulation of nuclear cAMP signaling and gene expression and how the regulation may affect the b2AR signaling in learning and memory (Aim 3). This proposed study will define the role of PDE4D5 in nuclear cAMP signaling, gene expression, and learning and memory, which not only offer new strategies to treat disorders associated with the CNS adrenergic system but also offer an example to study many other Gs-coupled receptors, such as dopamine receptors in the regulation of gene expression.

抽象的研究已经确定了磷酸二酯酶超家族（PDE）在水解营及其亚细胞分布。我们旨在探索PDE在差异调节中的作用在质膜和核中的营地信号。具体而言，我们将发现海马（HC）中CNSβ2-肾上腺素受体（B2AR）刺激下的核营地信号在学习和记忆过程中的神经元。有趣的是，PDE4抑制剂受益于啮齿动物的学习和记忆人类，表明PDE4可能控制核中βAR诱导的cAMP信号。 PDE4D同工型与成纤维细胞和心肌细胞中的β2AR到微细胞亚cAMP-PKA信号以及PDE4D5有关与核中的AKAP95/PKA复合物有关。我们的初步数据表明βAR刺激促进HC神经元中PDE4D5的核出口。 PDE4D5的这种搬迁取决于内体 GRK磷酸化的B2AR，对于将cAMP信号输送到核中是至关重要的。除了 GRK磷酸化的B2AR，我们最近表征了B2AR的另一个不同的亚群在HC神经元中激动剂刺激后，PKA磷酸化并位于PM。我们假设两个 B2AR亚群协同促进通过抑制了依赖PDE4D5的抑制了核营信号来自核。我们将表征PDE4D5依赖性调节的机制核营地信号传导和基因表达以及法规如何影响学习中的B2AR信号和内存（AIM 3）。这项拟议的研究将定义PDE4D5在核营地信号传导中的作用表达，学习和记忆，不仅提供了治疗与之相关的疾病的新策略中枢神经系统肾上腺素系统，但也提供了一个研究许多其他GS耦合受体的例子，例如基因表达调节中的多巴胺受体。