Signaling Scaffolds for Specificity in Neuromodulator Action

神经调节剂作用特异性的信号支架

• 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
• 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' 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

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 已提议为阿尔茨海默氏症和帕金森氏病具有治疗潜力。但是，b- 肾上腺受体（B-AR）暴露了高度复杂的药物效应。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 同时有害影响。我们旨在了解B2-肾上腺素受体（B2-AR）的信号传导特异性， 它们选择性耦合到不同细胞内信号蛋白的机制和 分子效应在不同条件下。我们发布的初步结果表明了信号 97 kDa（SAP97）的脚手架，突触相关蛋白作为海马中B2-AR信号的编排 神经元。具体而言，SAP97（S97B）Tethers B2-AR的B-异型和效应器电压门控钾 通道亚基KV1.1一起将B2-AR信号的激活转化为KV1.1的抑制作用及其去除 从树突表面（共同称为KV1.1抑制）。因此，B2AR诱导的KV1.1 抑制作用增加了树突状兴奋，并降低了长期突触潜力的诱导阈值。 给定B2-AR信号还可以调节AMPA接收器亚基GLUA1的磷酸化，但通过A 不同的信号支架，我们假设信号脚手架介导信号传导特异性和 相互作用可以用作特定的药物靶标。在此提案中，使用S97B/B2-AR/KV1.1 作为示例模型的复杂性，我们旨在获得机械洞察力a）潜水员B2-ar信号如何传导 事件受到特别调节； b）S97b/b2-ar/kv1.1复合物的分子成分是什么 成就信号传导特异性； c）S97b/b2-ar/kv1.1信号通路的行为相关性是什么 在老鼠中。重要的是，在SAP97占用神经元中，控制B2-AR依赖性树突状的信号通路 兴奋性受到约100％的渗透率的损害，从而使分析具有最小的混杂作用 功能冗余。我们提出的实验的结果将提供一组机械清晰的 治疗精神病，神经学，免疫或心血管疾病的药物靶标，也许更多 重要的是导致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 实现特定效应蛋白的有偏见和选择性法规，以调节突触传播和 可塑性。