Calcium Channels, CaMKII and Mechanisms of Excitation-Transcription Coupling
钙通道、CaMKII 和兴奋转录偶联机制
基本信息
- 批准号:10636887
- 负责人:
- 金额:$ 51.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAlzheimer&aposs DiseaseAreaAutomobile DrivingBehavioralBindingBrain DiseasesCalciumCalcium ChannelCell NucleusChemicalsChemosensitizationCommunicationCouplingCyclic AMP-Responsive DNA-Binding ProteinDendritesDendritic SpinesDepressed moodDevelopmentDiffusionDiltiazemEnzymesEventExcisionGene ExpressionGenetic TranscriptionGenomicsGlutamatesIn SituIndividualKineticsL-Type Calcium ChannelsLearningLightLinkMediatingMembraneMembrane PotentialsMemoryMicrofilamentsModelingMolecularMolecular ConformationMutationN-Methyl-D-Aspartate ReceptorsN-terminalNeuronal PlasticityNeuronsNimodipineNuclearNuclear AccidentsOpticsPatternPhasePhosphorylationPlayProteinsRoleSeriesSignal InductionSignal TransductionSiteSkeletal MuscleSourceStimulusSynapsesSynaptic TransmissionSynaptic plasticityTestingTimeTranscriptional ActivationTranscriptional RegulationTreesVariantVertebral columnWorkantagonistcalmodulin-dependent protein kinase IIdetectorexcitatory neuronexperimental studyfascinatein vivometermolecular dynamicsneuropsychiatric disorderneurotransmissionnovelpostsynapticrecruitresidenceresponsespatial memorysynergismtranscription factortransmission processvoltage
项目摘要
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+ channelCaMKII
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 channelCaMKII 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
项目成果
期刊论文数量(0)
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RICHARD W TSIEN其他文献
RICHARD W TSIEN的其他文献
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{{ truncateString('RICHARD W TSIEN', 18)}}的其他基金
Oxytocin Modulation of Neural Circuit Function and Behavior
催产素对神经回路功能和行为的调节
- 批准号:
10676011 - 财政年份:2022
- 资助金额:
$ 51.65万 - 项目类别:
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 - 财政年份:2022
- 资助金额:
$ 51.65万 - 项目类别:
Biophysical and Circuit Mechanisms of OXTR signaling
OXTR信号的生物物理和电路机制
- 批准号:
10438594 - 财政年份:2018
- 资助金额:
$ 51.65万 - 项目类别:
Oxytocin Modulation of Neural Circuit Function and Behavior
催产素对神经回路功能和行为的调节
- 批准号:
10220151 - 财政年份:2018
- 资助金额:
$ 51.65万 - 项目类别:
Oxytocin Modulation of Neural Circuit Function and Behavior
催产素对神经回路功能和行为的调节
- 批准号:
10438587 - 财政年份:2018
- 资助金额:
$ 51.65万 - 项目类别:
Oxytocin Modulation of Neural Circuit Function and Behavior
催产素对神经回路功能和行为的调节
- 批准号:
10705986 - 财政年份:2018
- 资助金额:
$ 51.65万 - 项目类别:
Oxytocin Modulation of Neural Circuit Function and Behavior - Revision - 3
催产素对神经回路功能和行为的调节 - 修订版 - 3
- 批准号:
10601831 - 财政年份:2018
- 资助金额:
$ 51.65万 - 项目类别: