Alpha2delta-mediated control of neuronal signaling
Alpha2delta 介导的神经信号传导控制
基本信息
- 批准号:10590759
- 负责人:
- 金额:$ 33.98万
- 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:2022-03-15 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAction PotentialsAcuteAtaxiaBindingBinding ProteinsBiological AssayBrainBuffersCNR1 geneCalciumCalcium ChannelCalcium SignalingCell membraneCellsCompensationComplexCoupledCouplingDataDevelopmentDiffuseDiseaseDisparateDrug ModulationDrug TargetingElectrophysiology (science)EndocannabinoidsEpilepsyFamilyFiberGenesHippocampusHomeostasisHumanIndividualInhibitory SynapseKnockout MiceLinkMediatingMediatorMembraneMigraineMolecularMusMutant Strains MiceMutationNeurologicNeuronsPharmaceutical PreparationsPhenotypePlayPotassium ChannelPresynaptic TerminalsProcessPropertyProtein FamilyProtein IsoformsProtein SubunitsProteinsPublishingPurkinje CellsRoleRunawaySignal TransductionSliceSourceSurfaceSynapsesSynaptic plasticityTestingVirusWhole-Cell Recordingsautism spectrum disordercell typedeafnessendocannabinoid signalingexperimental studygabapentinimprovedinsightloss of functionmind controlmutantnanonervous system disorderneuronal excitabilityneuropathologyneurotransmissionnovelpostsynapticpostsynaptic neuronspresynapticpreventprotein functionreceptorsynaptic functiontraffickingvesicular releasevoltagevoltage clamp
项目摘要
PROJECT SUMMARY
Intracellular calcium drives neuronal signaling and excitability, and appropriate spatial and temporal control
of neuronal calcium signals are required to prevent dysregulated control of brain activity, which can lead to
epileptic seizures. One of the primary sources of calcium in neurons is entry via voltage-gated calcium channels
on the cell membrane, which is then coupled to various effector mechanisms through co-localization of
channels and calcium-responsive proteins within the neuron. Two specific, but distinct, calcium-dependent
processes critical for maintaining brain homeostasis involve retrograde endocannabinoid signaling and the
action potential afterhyperpolarization. Endocannabinoids are produced postsynaptically by neurons in a
calcium-dependent manner, and then diffuse to presynaptic terminals where they bind to CB1 receptors and
powerfully inhibit vesicle release at numerous synapses. Separately, voltage-dependent calcium entry activates
nearby coupled calcium-dependent potassium channels, mediating the action-potential afterhyperpolarization
which accelerates cell repolarization and controls neuronal firing rates. For each of these phenomena, tight
functional coupling of calcium entry to these disparate effectors is critical in maintaining brain function.
While the specific cellular mechanisms responsible for controlling the appropriate localization of voltage-gated
calcium channels remain largely unknown, our preliminary data indicate a critical role for the alpha2delta
proteins in the functional coupling of calcium entry to effectors. These auxiliary calcium channel subunits help
traffic voltage-gated calcium channels to the neuronal surface membrane, but have otherwise remained
enigmatic despite clear association with neurologic diseases in humans and mice. We hypothesize that the
alpha2delta proteins are critical mediators of functional coupling between calcium entry and calcium-
dependent signaling throughout the brain. We propose to use genetically modified mice and
electrophysiological assays to define the roles of alpha2delta isoforms in 1) calcium-dependent retrograde
signaling from cerebellar Purkinje cells to their various synaptic inputs, 2) the control of excitability and
endocannabinoid signaling in the hippocampus, and 3) the molecular mechanisms underlying these
phenomena using molecular replacement strategies. Together, these experiments will lead to a greatly
enhanced appreciation of the function of this important class of calcium channel subunits, which we believe
can be leveraged to improve our ability to control runaway excitability in the brain in conditions such as
epileptic seizures.
项目摘要
细胞内钙驱动神经元信号传导和兴奋性,以及适当的空间和时间控制
神经元钙信号是防止大脑活动控制失调所必需的,这可能导致
癫痫发作神经元中钙的主要来源之一是通过电压门控钙通道进入
在细胞膜上,然后通过共定位与各种效应机制偶联,
神经元内的钙通道和钙反应蛋白。两种特异的,但不同的,钙依赖性的
维持大脑稳态的关键过程涉及逆行内源性大麻素信号传导,
超极化后动作电位内源性大麻素由神经元在突触后产生,
钙依赖性的方式,然后扩散到突触前末梢,在那里它们与CB 1受体结合,
在许多突触处有效抑制囊泡释放。另外,电压依赖性钙离子进入激活
附近的耦合钙依赖性钾通道,介导动作电位后超极化
其加速细胞复极并控制神经元放电率。对于每一种现象,紧
钙进入与这些不同的效应物的功能偶联在维持脑功能中是关键的。
虽然负责控制电压门控的适当定位的特定细胞机制,
钙通道在很大程度上仍然未知,我们的初步数据表明alpha 2 delta发挥着关键作用
蛋白质在钙进入效应器的功能耦合。这些辅助钙通道亚单位帮助
将电压门控钙通道运输到神经元表面膜,但在其他方面仍然存在
尽管与人类和小鼠的神经系统疾病有明确的联系,但这一点仍令人费解。我们假设
α 2 δ蛋白质是钙进入和钙-
在整个大脑中传递信号。我们建议使用转基因小鼠,
确定α 2 δ亚型在1)钙依赖性逆行性
小脑浦肯野细胞向其各种突触输入的信号传导,2)兴奋性的控制,
海马中的内源性大麻素信号传导,以及3)这些信号传导的分子机制。
现象使用分子置换策略。总之,这些实验将导致一个巨大的
增强了对这类重要的钙通道亚基功能的认识,我们相信,
可以用来提高我们在以下情况下控制大脑失控兴奋性的能力,
癫痫发作。
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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Eric Schnell其他文献
Eric Schnell的其他文献
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{{ truncateString('Eric Schnell', 18)}}的其他基金
Alpha2delta-mediated control of neuronal signaling
Alpha2delta 介导的神经信号传导控制
- 批准号:
10418233 - 财政年份:2022
- 资助金额:
$ 33.98万 - 项目类别:
Control of Circuit Hyperexcitability by Endogenous Opioids in Epilepsy
癫痫中内源性阿片类药物对回路过度兴奋的控制
- 批准号:
9891797 - 财政年份:2020
- 资助金额:
$ 33.98万 - 项目类别:
Control of Circuit Hyperexcitability by Endogenous Opioids in Epilepsy
癫痫中内源性阿片类药物对回路过度兴奋的控制
- 批准号:
10618918 - 财政年份:2020
- 资助金额:
$ 33.98万 - 项目类别:
Control of Circuit Hyperexcitability by Endogenous Opioids in Epilepsy
癫痫中内源性阿片类药物对回路过度兴奋的控制
- 批准号:
10454774 - 财政年份:2020
- 资助金额:
$ 33.98万 - 项目类别:
Functional contribution of adult-born neurons to epileptogenesis
成年神经元对癫痫发生的功能贡献
- 批准号:
9210540 - 财政年份:2016
- 资助金额:
$ 33.98万 - 项目类别:
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