Structural Studies of Vesicular Monoamine Transporters
囊泡单胺转运蛋白的结构研究
基本信息
- 批准号:8528735
- 负责人:
- 金额:$ 19.98万
- 依托单位:
- 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:2012-08-10 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:1-Methyl-4-phenylpyridiniumAlzheimer&aposs DiseaseAminesAmphetaminesAntibodiesAreaBindingBipolar DisorderBirthBrainBrain imagingCell membraneCellsCholesterolClinicalCocaineCollaborationsCoupledCrystallizationCytoplasmDataDependenceDetergentsDevelopmentDiseaseDopamineDrug AddictionDrug DesignEnhancersEpinephrineFluorescenceFundingGenetic PolymorphismGilles de la Tourette syndromeGlycerolGoalsGrantHeterogeneityHistamineHomologous GeneHuntington DiseaseHypertensionInsectaIntegral Membrane ProteinIon TransportKnockout MiceLaboratoriesLengthLinkLipidsMammalsMembraneMembrane ProteinsMolecularMolecular ConformationMolecular Sieve ChromatographyMonitorMood DisordersMovementMuramidaseMusMutagenesisNeuraxisNeuronsNeurotoxinsNeurotransmittersNorepinephrineParkinson DiseaseParkinsonian DisordersPatientsPhasePlayPoisonProcessProtein IsoformsProteinsProtonsPsychotic DisordersPublishingRattusReducing AgentsResearchReserpineResourcesRoleSchizophreniaSerotoninShapesSignal TransductionSodiumSpodoptera frugiperdaStructureSubstantia nigra structureSurfaceSynapsesSynaptic CleftSynaptic TransmissionSynaptic VesiclesTardive DyskinesiaTemperatureTestingTetrabenazineTherapeuticVesicleWorkYeastsanalogantiportbasedensitydesigndihydrotetrabenazinedirected evolutionhigh riskinhibitor/antagonistinsightinterestmonoaminemutantneuropsychiatryneurotransmitter releaseoverexpressionpresynapticradioligandresponsestability testingsuccesssymportertransport inhibitoruptakevacuolar H+-ATPasevesicular monoamine transportervesicular monoamine transporter 1vesicular monoamine transporter 2
项目摘要
DESCRIPTION (provided by applicant): Vesicular monoamine transporter 2 (VMAT2) is an integral membrane protein that plays a critical role in aminergic synaptic transmission by replenishing depleted neurotransmitter stores in presynaptic vesicles. It works by harnessing a pre-existing proton gradient generated by V-type ATPase to couple the uptake of one cytoplasmic cationic amine with the efflux of two luminal protons. Substrates include serotonin, dopamine, norepinephrine, epinephrine, and histamine. The significance of VMAT2 is underscored by the phenomenal levels (~500 mM) to which it concentrates its substrates inside the synaptic vesicle and by its active role in sequestering several toxic compounds from the neuronal cytoplasm. Currently-prescribed therapeutics include the inhibitors reserpine [RES] and tetrabenazine [TBZ]. RES is used as a second-line agent to treat hypertension and psychosis; TBZ is approved to treat the uncontrolled movements in Huntington's disease and the tics in Tourette's syndrome. Despite such clinical and pharmacological significance, very little is known about the structural basis for transport, ion-dependence, substrate recognition, and inhibition. A VMAT2 crystal structure would provide the crucial information and likely revolutionize the field. The goal of this proposal is to gather the preliminary data required for such a pursuit: to express, purify, and obtain diffraction-quality crystals of a eukaryotic VMAT2 homologue.
描述(由申请人提供):囊泡单胺转运蛋白2(VMAT2)是一种积分的膜蛋白,通过补充突触前囊泡中耗尽的神经递质存储,在AMINERGIC突触传播中起关键作用。它通过利用V型ATPase产生的先前存在的质子梯度来促进对一个细胞质阳离子胺的摄取与两个腔质子的外排。底物包括5-羟色胺,多巴胺,去甲肾上腺素,肾上腺素和组胺。 VMAT2的重要性是由它将其底物浓缩在突触囊泡内的底物以及其在隔离神经元细胞质中几种有毒化合物中的积极作用的现象水平(〜500 mm)强调的。当前处方的治疗剂包括抑制剂治疗[RES]和四苯甲嗪[TBZ]。 RES用作治疗高血压和精神病的二线药物; TBZ被批准用于治疗亨廷顿氏病和图雷特综合症中的抽动中的不受控制的运动。尽管临床和药理意义如此,但对运输,离子依赖性,底物识别和抑制的结构基础知之甚少。 VMAT2晶体结构将提供关键信息,并可能彻底改变该领域。该提案的目的是收集这种追求所需的初步数据:表达,净化和获得真核VMAT2同源物的衍射质量晶体。
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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SATINDER Kaur SINGH其他文献
SATINDER Kaur SINGH的其他文献
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{{ truncateString('SATINDER Kaur SINGH', 18)}}的其他基金
Structure and Function of a Serotonin Transporter
血清素转运蛋白的结构和功能
- 批准号:
8773997 - 财政年份:2014
- 资助金额:
$ 19.98万 - 项目类别:
Structure and Function of a Serotonin Transporter
血清素转运蛋白的结构和功能
- 批准号:
8910786 - 财政年份:2014
- 资助金额:
$ 19.98万 - 项目类别:
Structure and Function of a Serotonin Transporter
血清素转运蛋白的结构和功能
- 批准号:
9270606 - 财政年份:2014
- 资助金额:
$ 19.98万 - 项目类别:
Structural Studies of Vesicular Monoamine Transporters
囊泡单胺转运蛋白的结构研究
- 批准号:
8360957 - 财政年份:2012
- 资助金额:
$ 19.98万 - 项目类别:
Transport and Inhibition in a Biogenic Amine Transporter
生物胺转运蛋白的转运和抑制
- 批准号:
7451429 - 财政年份:2008
- 资助金额:
$ 19.98万 - 项目类别:
Transport and Inhibition in a Biogenic Amine Transporter
生物胺转运蛋白的转运和抑制
- 批准号:
8272595 - 财政年份:2008
- 资助金额:
$ 19.98万 - 项目类别:
Transport and Inhibition in a Biogenic Amine Transporter
生物胺转运蛋白的转运和抑制
- 批准号:
8111165 - 财政年份:2008
- 资助金额:
$ 19.98万 - 项目类别:
Transport and Inhibition in a Biogenic Amine Transporter
生物胺转运蛋白的转运和抑制
- 批准号:
8066133 - 财政年份:2008
- 资助金额:
$ 19.98万 - 项目类别:
Transport and Inhibition in a Biogenic Amine Transporter
生物胺转运蛋白的转运和抑制
- 批准号:
7623163 - 财政年份:2008
- 资助金额:
$ 19.98万 - 项目类别:
Transport and Inhibition in a Biogenic Amine Transporter
生物胺转运蛋白的转运和抑制
- 批准号:
7871107 - 财政年份:2008
- 资助金额:
$ 19.98万 - 项目类别:
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