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.

抽象的 在神经元兴奋转录（E-T）耦合中，体细胞树突膜上的电信号驱动 数十或数百微米外的细胞核中的转录激活。 E-T 耦合对于长期运行至关重要 术语适应、突触可塑性、发育和记忆；它可能会因大脑疾病而出错。电压门控 L 型 Ca2+ 通道 (LTCC) 在 E-T 耦合中起主导作用。打开这些 Ca2+ 通道会启动 导致核转录因子 CREB（Ca2+- 和 cAMP- 反应元件）激活的级联反应 结合蛋白），因其对学习和记忆的重要性而被广泛研究。该提案涉及 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介导 E-T 耦合：Ca2+ 的局部升高 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 Ca2+ 流入受阻，VΔC 也会协同增强 CaMKII 的动员 树突棘由 NMDA 受体刺激启动，并大大增强了磷酸化 CREB ​​反应。 谷氨酸能输入（NMDAR）和电信号传导（VΔC）之间的这种合作就像一个 时间邻近检测器，对突触可塑性可能具有重要意义。我们将解决有关的新问题 机械成分、对突触和分子动力学的影响以及神经元信号传导 次区域。首先，我们将设计L型通道以确定Ca2+通道CaMKII 沟通发生了。其次，我们将测试 CaMKII 之间多个步骤的机械模型 释放和动员到突触位点、驻留在 NMDAR 以及最终的构象敏感 LTCC 诱捕。第三，我们将描绘局部次区域控制核转录并衡量 突触 L 型通道CaMKII 信号传导对突触强度的即时和 24 小时变化的影响 与多种脑部疾病的相关性，包括神经精神疾病和阿尔茨海默病。