The Potassium Channel Slowpoke and the molecular mechanisms of Neuronal Homeost.
钾通道慢马和神经元稳态的分子机制。
基本信息
- 批准号:9302475
- 负责人:
- 金额:$ 22.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:Alcohol dependenceAlzheimer&aposs DiseaseAsorbicapBindingBiochemistryBypassC-terminalCalciumCenters of Research ExcellenceCo-ImmunoprecipitationsCognitionComplementary DNAConfocal MicroscopyDiseaseDrosophila genusEnsureEpilepsyFailureFinancial compensationFutureGeneralized EpilepsyGeneticGoalsHeartHomeostasisHumanImageImmunohistochemistryIon ChannelIonsLearningLifeLinkMemoryMethodsMicroscopyModificationMolecularMolecular GeneticsMutationNerveNeurobiologyNeuromuscular JunctionNeuronal PlasticityNeuronsParoxysmal DyskinesiasPharmacologyPotassium ChannelProcessPropertyPuerto RicoRegulationResearchRestSchizophreniaSecureSeriesSignal TransductionSignaling MoleculeSkeletal MuscleSynapsesSynaptic plasticitySystemTailTestingTherapeuticTimeTransgenic OrganismsUniversitiesUp-Regulationactive controladdictionautism spectrum disorderdosageexperimental studyflexibilityflymutantneuronal circuitryneurotransmitter releasenovelpostsynapticpresynapticquantumscaffoldsynaptic functiontooltwo-photon
项目摘要
. PROJECT SUMMARY (See instructions):
During our life time, homeostatic signaling systems secure the integrity of neuronal circuits while allowing some flexibility that will be the basis for processes of cognition, learning and memory. It is therefore not surprising that a series of neurobiological diseases (autism spectrum disorder, Alzheimer's disease and schizophrenia, among them) have been linked to alterations in homeostatic mechanisms. Despite the tremendous importance of understanding neuronal homeostasis and how homeostatic signaling systems interact with neuronal plasticity, we know close to nothing about the molecular mechanisms underlying synaptic homeostasis. We have recently discovered that the highly conserved BK-type K+ channel, slowpoke (slo) is essential to the homeostatic control of synaptic function. This study will define a new function for slo while characterizing a new molecular mechanism for the homeostatic stabilization of neuronal function. In human, mutation in slo has been implicated in generalized epilepsy and paroxysmal dyskinesia, slo is also known to control the active properties of neurons and skeletal muscles, to be essential to aspects of synaptic plasticity and alcohol addiction, and to bind to really important signaling molecules, including Ca2+ channels. This study will combine quintal analysis of different mutant backgrounds, pharmacology, molecular genetics, biochemistry and activity dependent Ca2+ imaging using two-photon microscopy to show that (1)- the modification of Ca2+ influx is the mechanism at the heart of homeostatic plasticity and that this mechanism depends on presynaptic slo. (2)- Slo conductance is not required to perform this function; the Slo C-terminus tail is sufficient to restore homeostasis, illustrating a new essential function for the regulatory Slo sequences. (3)- the Slo C-terminus tail interacts with the Ca2+ channel responsible for neurotransmitter release, CaV2.1 (Cae). This interaction is required for the upregulation of Cae during synaptic homeostasis.
.项目总结(见说明):
在我们的一生中,稳态信号系统确保了神经元回路的完整性,同时允许一些灵活性,这将是认知,学习和记忆过程的基础。因此,一系列神经生物学疾病(其中包括自闭症谱系障碍、阿尔茨海默病和精神分裂症)与体内平衡机制的改变有关,这并不奇怪。尽管了解神经元内稳态以及内稳态信号系统如何与神经元可塑性相互作用非常重要,但我们对突触内稳态的分子机制几乎一无所知。我们最近发现,高度保守的BK型K+通道,慢波(slowpoke)是必不可少的突触功能的稳态控制。这项研究将定义一个新的功能,同时表征一个新的分子机制的稳态稳定的神经元功能。在人类中,β-淀粉样蛋白的突变与全身性癫痫和阵发性运动障碍有关,β-淀粉样蛋白还已知控制神经元和骨骼肌的活性特性,对突触可塑性和酒精成瘾方面至关重要,并与真正重要的信号分子结合,包括Ca 2+通道。本研究将结合联合收割机对不同突变背景的五分位分析、药理学、分子遗传学、生物化学和使用双光子显微镜的活性依赖性Ca 2+成像,以表明(1)-Ca 2+内流的修饰是稳态可塑性的核心机制,并且该机制依赖于突触前突触。(2)-Slo电导不需要执行此功能; Slo C-末端尾部足以恢复稳态,说明调节Slo序列的新的基本功能。(3)-SloC-末端尾与负责神经递质释放的Ca 2+通道CaV2.1(Cae)相互作用。这种相互作用是突触稳态过程中Cae上调所必需的。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Bruno Marie其他文献
Bruno Marie的其他文献
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{{ truncateString('Bruno Marie', 18)}}的其他基金
Molecular mechanisms underlying the choice between homeostasis and activity-dependent plasticity at the synapse
突触稳态和活动依赖性可塑性之间选择的分子机制
- 批准号:
10020797 - 财政年份:2019
- 资助金额:
$ 22.82万 - 项目类别:
Encoding Long Term Stability of Neuronal Function
编码神经元功能的长期稳定性
- 批准号:
8334009 - 财政年份:2011
- 资助金额:
$ 22.82万 - 项目类别:
Encoding Long Term Stability of Neuronal Function
编码神经元功能的长期稳定性
- 批准号:
8145899 - 财政年份:2011
- 资助金额:
$ 22.82万 - 项目类别:
Encoding Long Term Stability of Neuronal Function
编码神经元功能的长期稳定性
- 批准号:
8533053 - 财政年份:2011
- 资助金额:
$ 22.82万 - 项目类别:
The Potassium Channel Slowpoke and the molecular mechanisms of Neuronal Homeost.
钾通道慢马和神经元稳态的分子机制。
- 批准号:
8465622 - 财政年份:
- 资助金额:
$ 22.82万 - 项目类别:
The Potassium Channel Slowpoke and the molecular mechanisms of Neuronal Homeost.
钾通道慢马和神经元稳态的分子机制。
- 批准号:
8687681 - 财政年份:
- 资助金额:
$ 22.82万 - 项目类别:
The Potassium Channel Slowpoke and the molecular mechanisms of Neuronal Homeost.
钾通道慢马和神经元稳态的分子机制。
- 批准号:
8912496 - 财政年份:
- 资助金额:
$ 22.82万 - 项目类别: