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: 10636887
• 负责人: RICHARD W TSIEN
• 金额: $ 51.65万
• 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/10636887
• 关键词: Address; Alzheimer' s Disease; Area; Automobile Driving; Behavioral; Binding; Brain Diseases; Calcium; Calcium Channel; Cell Nucleus; Chemicals; Chemosensitization; Communication; Coupling; Cyclic AMP-Responsive DNA-Binding Protein; Dendrites; Dendritic Spines; Depressed mood; Development; Diffusion; Diltiazem; Enzymes; Event; Excision; Gene Expression; Genetic Transcription; Genomics; Glutamates; In Situ; Individual; Kinetics; L-Type Calcium Channels; Learning; Light; Link; Mediating; Membrane; Membrane Potentials; Memory; Microfilaments; Modeling; Molecular; Molecular Conformation; Mutation; N-Methyl-D-Aspartate Receptors; N-terminal; Neuronal Plasticity; Neurons; Nimodipine; Nuclear; Nuclear Accidents; Optics; Pattern; Phase; Phosphorylation; Play; Proteins; Role; Series; Signal Induction; 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; meter; molecular dynamics; neuropsychiatric disorder; neurotransmission; novel; postsynaptic; 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，体树突膜上的电信号驱动 在几十或几百微米之外的细胞核中进行转录激活。E-T耦合对于长期的 术语适应，突触可塑性，发育和记忆;它可以在大脑疾病中出错。电压依赖 L型钙通道（LTCCs）在E-T偶联中起主导作用。打开这些Ca 2+通道， 引起核转录因子CREB（Ca 2 +-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大量研究。这项建议涉及 将LTCC激活与CREB磷酸化和其他核事件联系起来的信号传导机制。 我们最近发现，兴奋性神经元使用两种不同的信号来介导E-T耦合：局部Ca 2+升高 LTCC的电压依赖性构象变化（VΔC），类似于触发收缩的VΔC 骨骼肌即使LTCC Ca 2+内流被阻断，VΔC协同增强CaMKII动员， 树突棘启动的NMDA受体刺激，大大增强磷酸化CREB反应。 神经元能输入（NMDAR）和电信号（VΔC）之间的这种合作就像一个 时间邻近检测器，可能对突触可塑性有重要意义。我们将讨论新的问题， 机制成分，对突触和分子动力学的影响，以及神经元的信号传导 分区域.首先，我们将设计L型通道，以确定Ca 2+通道如何与CaMKII结合 沟通就来了。其次，我们将测试CaMKII之间多个步骤的机械模型， 释放和动员到突触部位，其停留在NMDAR和其最终的构象敏感性LTCC 诱捕第三，我们将描绘局部亚区控制核转录的潜力，并测量核转录的可能性。 突触L-型通道β CaMKII信号传导对突触强度即刻和24小时变化的影响， 与多种脑部疾病相关，包括神经精神疾病和阿尔茨海默病。