Signaling Scaffolds for Specificity in Neuromodulator Action

神经调节剂作用特异性的信号支架

基本信息

批准号：
10582659
负责人：
Oliver Schlueter
金额：
$ 36.22万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10582659
关键词：
A kinase anchoring protein AMPA Receptors Adrenergic Agents Adrenergic Receptor Alzheimer&apos s Disease Arousal Association Learning Attention Behavior assessment Behavioral Binding Biological C-terminal Cardiovascular Diseases Cell model Cells Chemosensitization Clinical Complex Coupled Cyclic AMP-Dependent Protein Kinases DLG1 gene Dendrites Disinhibition Drug Modulation Drug Targeting Electrophysiology (science)Emotional Endocytosis Event Excision Exhibits G-Protein-Coupled Receptors Gene Transfer Glutamate Receptor Hippocampus Immune System Diseases Impairment Individual Intracellular Signaling Proteins Ion Channel Knockout Mice Lead Learning Ligands Link Mediating Memory Mental disorders Modeling Molecular Multiprotein Complexes Mus Nerve Degeneration Neuromodulator Neurons Norepinephrine Organ Outcome Parkinson Disease Penetrance Peptides Pharmacologic Substance Pharmacology Phosphorylation Postsynaptic Membrane Process Property Protein Family Protein Isoforms Proteins Psychiatric therapeutic procedure Publishing RNA Interference Regulation Scheme Signal Pathway Signal Transduction Signal Transduction Pathway Site Specific qualifier value Specificity Surface Synapses Synaptic Transmission Synaptic plasticity Therapeutic Time Viral Voltage-Gated Potassium Channel Work adenylate clinical application cognitive enhancement cognitive function experimental study heuristics hippocampal pyramidal neuron improved insight loss of function membrane-associated guanylate kinase mutant nervous system disorder neural circuit novel paralogous gene pharmacologic postsynaptic prevent receptor reconstitution recruit scaffold segregation synaptic function synaptogenesis

项目摘要

Abstract b2-adrenoceptor signaling is critical for adrenergic regulation of synaptic plasticity and neurodegeneration, and has been proposed to have therapeutic potentials for Alzheimer’s and Parkinson’s diseases. However, b- adrenoceptors (b-ARs) exhibit highly complicated pharmaceutical effects. This is exemplified by clinical results, in which b-AR drugs modulate receptor paralogs in different organs to elicit both therapeutic and clinically harmful effects at the same time. We aim to understand the signaling specificity of b2-adrenoceptors (b2-ARs), mechanisms through which they are selectively coupled to different intracellular signaling proteins and molecular effectors under different conditions. Our published and preliminary results manifest the signaling scaffold, synapse-associated protein of 97 kDa (SAP97) as an orchestrator of b2-AR signaling in hippocampal neurons. Specifically, the b-isoform of SAP97 (S97b) tethers b2-ARs and the effector voltage-gated potassium channel subunit Kv1.1 together to transduce activation of b2-AR signaling into inhibition of Kv1.1 and its removal from the dendrite surface (collectively referred to as Kv1.1 inhibition). Consequently, b2-AR-induced Kv1.1 inhibition increases dendritic excitability and lowers the induction threshold for long-term synaptic potentiation. Given b2-AR-signaling also regulates the phosphorylation of the AMPA receptor subunit GluA1, but through a different signaling scaffold, we hypothesize that signaling scaffolds mediate the signaling specificity and the interactions can be used as specific pharmacological targets. In this proposal, using the S97b/b2-AR/Kv1.1 complex as an exemplary model, we aim to gain mechanistic insights into a) how the diverse b2-AR signaling events are specifically regulated; b), what the molecular components of the S97b/b2-AR/Kv1.1 complex are to achieve signaling specificity; and c) what are the behavioral correlates of the S97b/b2-AR/Kv1.1 signaling pathway in mice. Importantly, in SAP97-lacking neurons, the signaling pathway governing b2-AR dependent dendritic excitability is impaired with a ~100% penetrance, allowing an analysis with minimal confounding effects of functional redundancy. The outcomes of our proposed experiments will provide a set of mechanistically clear drug targets for treating psychiatric, neurological, immunological or cardiovascular disorders, and perhaps more importantly lead to a novel and generalizable molecular scheme, through which G-protein-coupled receptors achieve biased and selective regulations of specific effector proteins to modulate synaptic transmission and plasticity.

抽象的 b2-肾上腺素受体信号传导对于突触可塑性和神经变性的肾上腺素能调节至关重要，已被认为具有治疗阿尔茨海默病和帕金森病的潜力。肾上腺素受体（b-AR）表现出高度复杂的药物作用，临床结果证明了这一点。其中 b-AR 药物调节不同器官中的受体旁系同源物，以引起治疗和临床效果我们的目标是了解 b2-肾上腺素受体 (b2-AR) 的信号传导特异性，它们选择性地与不同的细胞内信号蛋白偶联的机制我们发表的初步结果表明了不同条件下的分子效应。支架，97 kDa 的突触相关蛋白 (SAP97) 作为海马 b2-AR 信号传导的协调者具体来说，SAP97 (S97b) 的 b-异构体连接 b2-AR 和效应电压门控钾。通道亚基 Kv1.1 一起将 b2-AR 信号传导的激活转导为 Kv1.1 的抑制及其去除从树突表面（统称为 Kv1.1 抑制）检查，b2-AR 诱导 Kv1.1。抑制增加树突的兴奋性并降低长期突触增强的诱导阈值。 b2-AR 信号传导还调节 AMPA 受体亚基 GluA1 的磷酸化，但通过不同的信号支架，我们认为信号支架介导信号特异性和在本提案中，使用 S97b/b2-AR/Kv1.1 可以用作特定的药理学靶点。作为一个示例性模型，我们的目标是获得以下机制的见解：a) 多样化的 b2-AR 信号传导如何 b) S97b/b2-AR/Kv1.1 复合物的分子成分有何作用？实现信号特异性；c) S97b/b2-AR/Kv1.1 信号通路的行为相关性是什么重要的是，在 SAP97 系带神经元中，控制 b2-AR 依赖性树突的信号通路。兴奋性受到约 100% 外显率的影响，允许以最小的混杂效应进行分析我们提出的实验结果将提供一组机械上清晰的结果。用于治疗精神、神经、免疫或心血管疾病等疾病的药物靶标重要的是导致了一种新颖且可推广的分子方案，通过该方案G蛋白偶联受体实现对特定效应蛋白的有偏性和选择性调节，以调节突触传递和可塑性。