Coupled LTP-dependent trafficking of synaptic SK channels and NMDARs

突触 SK 通道和 NMDAR 的耦合 LTP 依赖性运输

基本信息

批准号：
8471779
负责人：
JOHN P ADELMAN
金额：
$ 29.26万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8471779
关键词：
14-3-3 Proteins Affect Antibodies Binding Binding Proteins Binding Sites Biochemical Biological Assay Brain Brain Diseases C-terminal Calcium-Activated Potassium Channel Cell model Cells Chemicals Chemosensitization Chinese Hamster Ovary Cell Cognition Disorders Cognitive Coupled Cyclic AMP-Dependent Protein Kinases DNA Sequence Rearrangement Dendritic Spines Electrophysiology (science)Endocytosis Endosomes Epitopes Excitatory Postsynaptic Potentials Family Hippocampus (Brain)Hour Immunoelectron Microscopy In Vitro Intervention Knockout Mice Learning Light Link Long-Term Potentiation Measures Membrane Potentials Memory Modeling Molecular N-Methylaspartate Neurons Pathway interactions Peptides Phosphorylation Point Mutation Preparation Process Proteins Recovery Relative (related person)Research Scaffolding Protein Serine Slice Synapses Synaptic plasticity Testing Time Vertebral column Vesicle Western Blotting Whole-Cell Recordings Work base clinical application density design hippocampal pyramidal neuron in vivo innovation memory encoding mutant neurotransmission novel overexpression postsynaptic reconstitution research study response therapeutic target trafficking

项目摘要

DESCRIPTION (provided by applicant): Synaptic Ca2+-activated K+ channels, SK2 channels, influence neurotransmission, synaptic plasticity, and learning and memory. Blocking SK channel activity facilitates synaptic plasticity and learning and memory while overexpressing SK2 or pharmacologically increasing SK channel activity impairs these processes. We discovered the molecular and cellular mechanisms that are likely responsible for the effects of SK2 channels on synaptic plasticity, the leading model for cellular changes underlying learning and memory. We showed that the activity of SK2 channels in the dendritic spines of hippocampal CA1 pyramidal neurons is coupled to NMDAR activity. Synaptically evoked Ca2+ entry into spines activates synaptic SK2 channels that repolarize the spine membrane potential, thereby favoring Mg2+ re-block of NMDARs, and thus limiting Ca2+ influx through NMDARs that is crucial to the induction of synaptic plasticity. In addition we showed that plasticity-dependent trafficking of SK2 channels itself contributes to the expression of NMDAR-dependent long-term potentiation. New results suggest that SK2 channel trafficking is linked to NMDAR trafficking that is orchestrated and coordinated by a novel family of synaptic scaffolding proteins to affect synaptic dynamics. We will use an integrated repertoire of electrophysiology in fresh brain slice preparations and recordings from transfected cells, biochemical pull-down assays and reconstitutions experiments, and innovative immuno-electron microscopy to examine the molecular and cellular mechanisms that engender the orchestrated trafficking of SK2 channels and NMDARs. The results have profound implications for novel interventional strategies to treat a wide range of cognitive disorders.

描述（由申请人提供）：突触CA2+激活的K+通道，SK2通道，影响神经传递，突触可塑性以及学习和记忆。阻止SK通道活动有助于突触可塑性，学习和记忆，同时过表达SK2或在药理上增加SK通道活动会损害这些过程。我们发现了可能导致SK2通道对突触可塑性的影响的分子和细胞机制，这是学习和记忆的细胞变化的主要模型。我们表明，海马CA1锥体神经元的树突状刺中SK2通道的活性与NMDAR活性耦合。突触诱发的Ca2+进入棘突激活了使脊柱膜电位复制的突触SK2通道，从而有利于NMDAR的MG2+重新块，从而限制了Ca2+通过NMDAR的NMDAR，这对于诱导突触可塑性至关重要。此外，我们表明，SK2通道的可塑性依赖性运输本身有助于NMDAR依赖性长期增强的表达。新的结果表明，SK2渠道贩运与NMDAR贩运有关，NMDAR贩运是由新型突触脚手架蛋白系列和协调的，以影响突触动态。我们将在新鲜的脑切片制剂和转染细胞的录音中，生化下拉的测定法和重新构造实验以及创新的免疫电子显微镜检查，以检查分子和细胞机制，从而检查Sk2通道和NMDARS的分子机制，以检查分子和细胞机制。结果对治疗多种认知障碍的新型介入策略具有深远的影响。