Calcium Channels, CaMKII and Mechanisms of Excitation-Transcription Coupling

钙通道、CaMKII 和兴奋转录偶联机制

• 批准号: 10522762
• 负责人: RICHARD W TSIEN
• 金额: $ 49.8万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522762
• 关键词: Address; Alzheimer' s Disease; Area; Automobile Driving; Behavioral; Binding; Brain Diseases; CREB1 gene; Calcium; Calcium Channel; Cell Nucleus; Chemicals; Chemosensitization; Communication; Coupling; Cyclic AMP-Responsive DNA-Binding Protein; Dendrites; Dendritic Spines; Depressed mood; Development; Diffuse; Diffusion; Diltiazem; Enzymes; Event; Excision; Gene Expression; Genetic Transcription; Genomics; Glutamates; In Situ; Individual; Kinetics; L-Type Calcium Channels; Learning; Light; Link; Masks; Mediating; Membrane; Membrane Potentials; Memory; Microfilaments; Modeling; Molecular; Molecular Conformation; Mutation; N-Methyl-D-Aspartate Receptors; N-terminal; Neurons; Nimodipine; Nuclear; Nuclear Accidents; Optics; Pattern; Phase; Phosphorylation; Play; Proteins; Role; Series; Signal Transduction; Site; Skeletal Muscle; Source; Stimulus; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Time; Transcriptional Activation; Transcriptional Regulation; Trees; Variant; Vertebral column; Work; antagonist; calmodulin-dependent protein kinase II; detector; excitatory neuron; experimental study; fascinate; in vivo; molecular dynamics; neuropsychiatric disorder; neurotransmission; novel; postsynaptic; quantum; recruit; residence; response; spatial memory; synergism; transcription factor; transmission process; voltage

ABSTRACT In neuronal excitation-transcription (E-T) coupling, electrical signals at somatodendritic membranes drive transcriptional activation in the nucleus, tens or hundreds of micrometers away. E-T coupling is critical for long- term adaptation, synaptic plasticity, development and memory; it can go awry in brain disorders. Voltage-gated L-type Ca2+ channels (LTCCs) play a dominant role in E-T coupling. Switching on these Ca2+ channels initiates a cascade that causes activation of a nuclear transcription factor CREB (Ca2+- and cAMP- response element binding protein), heavily studied because of its importance for learning and memory. This proposal concerns signaling mechanisms that connect activation of LTCCs to CREB phosphorylation and other nuclear events. We recently found that excitatory neurons use two distinct signals to mediate E-T coupling: a local rise in Ca2+ and a voltage-dependent conformational change (VΔC) of the LTCC, akin to the VΔC that triggers contraction of skeletal muscle. Even with LTCC Ca2+ influx blocked, VΔC synergistically augmented CaMKII mobilization to dendritic spines initiated by NMDA receptor stimulation and greatly enhanced the phospho-CREB response. Such cooperation between glutamatergic input (NMDAR) and electrical signaling (VΔC) operates like a temporal proximity detector, of likely significance for synaptic plasticity. We will address new questions about mechanistic components, impact on synaptic and molecular dynamics, and signaling from neuronal subregions. First, we will make designer L-type channels to determine how Ca2+ channelCaMKII communication comes about. Second, we will test a mechanstic model for the multiple steps between CaMKII liberation and mobilization to synaptic sites, its dwell at NMDARs and its eventual conformation-sensitive LTCC trapping. Third, we will delineate the potency of local subregions to control nuclear transcription and gauge the impact of synaptic L-type channelCaMKII signaling on immediate and 24 h changes in synaptic strength, of relevance to multiple brain disorders, including neuropsychiatric diseases and Alzheimer’s disease.

摘要 在神经元兴奋-转录(E-T)偶联中，躯体树突膜上的电信号驱动 在几十或数百微米外的细胞核内转录激活。E-T耦合对于长时间的 术语适应、突触可塑性、发育和记忆；它可能在大脑紊乱时出错。电压门控 L型钙通道(LTCC)在E-T偶联中起主导作用。开启这些钙离子通道启动 引起核转录因子CREB(钙离子和cAMP反应元件)激活的级联反应 结合蛋白)，由于其对学习和记忆的重要性而被广泛研究。这项提议涉及到 将LTCC激活与CREB磷酸化和其他核事件联系起来的信号机制。 我们最近发现，兴奋性神经元使用两种不同的信号来调节E-T偶联：局部钙离子升高 和电压相关的LTCC的构象变化(VΔC)，类似于触发收缩的VΔC 骨骼肌。即使在LTCC钙内流被阻断的情况下，VΔC也协同增强了CaMKII的动员 树突棘在NMDA受体刺激下启动，并极大地增强磷酸化CREB反应。 谷氨酸能传入(NMDAR)和电信号(VΔC)之间的这种合作就像 可能对突触可塑性有重要意义的时间接近探测器。我们将解决有关以下方面的新问题 机械成分，对突触和分子动力学的影响，以及来自神经元的信号 子区域。首先，我们会让设计师L类通道来确定钙通道是如何实现的 交流随之而来。其次，我们将测试CaMKII之间的多个步骤的机械传递模型 对突触部位的释放和动员、其在NMDAR的驻留及其最终构象敏感型LTCC 诱捕。第三，我们将描绘控制核转录的局部亚区的效力，并测量 突触L型通道CaMKII信号对突触即刻和24小时突触强度变化的影响 与多种脑部疾病相关，包括神经精神疾病和阿尔茨海默病。