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磷酸二酯酶 (PDE) 超家族在我们的目的是探索 PDE 在差异调节中的作用。具体来说，我们将揭示质膜和细胞核中 cAMP 信号的调节。海马 (HC) 中枢神经系统 β2 肾上腺素能受体 (b2AR) 刺激下的核 cAMP 信号研究表明，PDE4 抑制剂有利于啮齿类动物的学习和记忆。和人类，表明 PDE4 可能控制细胞核中 βAR 诱导的 cAMP 信号。与 β2AR 相关，可微调成纤维细胞和肌细胞中的亚细胞 cAMP-PKA 信号，以及 PDE4D5 与细胞核中的 AKAP95/PKA 复合物相关。我们的初步数据表明 βAR 刺激。促进 HC 神经元中 PDE4D5 的核输出 PDE4D5 的这种重新定位取决于内体。 GRK 磷酸化 b2AR，对于将 cAMP 信号传递至细胞核至关重要。 GRK 磷酸化 b2AR，我们最近表征了 b2AR 的另一个独特亚群，它们是在 HC 神经元中受激动剂刺激后，PKA 被磷酸化并定位于 PM。我们追踪了这两个神经元。 b2AR 亚群通过抑制蛋白 3 依赖的 PDE4D5 输出协同促进核 cAMP 信号我们将描述 PDE4D5 依赖性调节的机制。核 cAMP 信号传导和基因表达以及调节如何影响学习中的 b2AR 信号传导和记忆（目标 3）。这项研究将确定 PDE4D5 在核 cAMP 信号传导、基因中的作用。表达、学习和记忆，这不仅提供了治疗与相关疾病相关的新策略 CNS 肾上腺素能系统，还提供了研究许多其他 Gs 偶联受体的示例，例如多巴胺受体参与基因表达的调节。