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: 10350625
• 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/10350625
• 关键词: A kinase anchoring protein; AMPA Receptors; Adrenergic Agents; Adrenergic Receptor; Alzheimer' s Disease; Arousal; Attention; Behavioral; Binding; Biological; C-terminal; Cardiovascular Diseases; Cardiovascular system; Cell model; Cells; Chemosensitization; Clinical; Complex; Coupled; Cyclic AMP-Dependent Protein Kinases; DLG1 gene; Dendrites; Disinhibition; Drug Targeting; Electrophysiology (science); Emotional; Endocytosis; Event; Excision; Exhibits; G-Protein-Coupled Receptors; Gene Transfer; Glutamates; Hippocampus (Brain); Immune System Diseases; Immunologics; Impairment; Individual; Intracellular Signaling Proteins; Ion Channel; Knock-out; Lead; Learning; Ligand Binding; Ligands; Link; Mediating; Memory; Mental disorders; Modeling; Molecular; Multiprotein Complexes; Mus; Nerve Degeneration; Neurologic; Neuromodulator; Neurons; Norepinephrine; Organ; Outcome; Parkinson Disease; Penetrance; Peptides; Pharmaceutical Preparations; 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; base; beta-2 Adrenergic Receptors; classical conditioning; 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; postsynaptic; prevent; receptor; reconstitution; recruit; scaffold; segregation; synaptic function

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.

摘要 β 2-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， 已被提出具有治疗阿尔茨海默病和帕金森病的潜力。但是，B- 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， 有害影响与此同时我们的目的是了解β 2-肾上腺素受体（β 2-AR）的信号特异性， 它们选择性地与不同的细胞内信号蛋白偶联的机制， 不同条件下的分子效应器。我们发表的和初步的结果表明， 支架，97 kDa突触相关蛋白（SAP 97）作为海马中b2-AR信号传导的协调者 神经元具体而言，SAP 97的b-同种型（S97 b）系链b2-AR和效应子电压门控钾通道。 通道亚基Kv1.1一起将b2-AR信号传导的激活转化为Kv1.1的抑制及其去除 从树突表面（统称为Kv1.1抑制）。因此，b2-AR诱导的Kv1.1 抑制增加树突兴奋性并降低长期突触增强的诱导阈值。 鉴于b2-AR信号也调节AMPA受体亚基GluA 1的磷酸化，但通过一个磷酸化的途径。 不同的信号传导支架，我们假设信号传导支架介导信号传导特异性， 相互作用可以用作特定的药理学靶点。在本提案中，使用S97 b/b2-AR/Kv1.1 作为一个复杂的示范性模型，我们的目标是获得机制的见解a）如何多样的b2-AR信号转导 事件受到特异性调节; B）S97 B/b2-AR/Kv1.1复合物的分子组分是什么， 实现信号传导特异性;以及c）S97 b/b2-AR/Kv1.1信号传导途径的行为相关性是什么 对小鼠重要的是，在SAP 97缺乏的神经元中，控制b2-AR依赖性树突状细胞的信号通路， 兴奋性以~100%的波动率受损，允许在最小混杂效应的情况下进行分析， 功能冗余我们提出的实验的结果将提供一组机械上清晰的 治疗精神、神经、免疫或心血管疾病的药物靶点， 重要的是导致了一种新的和可推广的分子方案，通过该方案，G-蛋白偶联受体 实现特异性效应蛋白的偏向性和选择性调节以调节突触传递， 可塑性