Modulators of CaV1.3 Ca2+ regulation
Modulators of CaV1.3 Ca2+ regulation
批准号:
8542901
负责人:
DAVID T YUE
金额:
$3.93万
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
项目状态:
已结题
起止时间:
2012-09-10 至 2014-07-31
关键词:
Adverse effectsAffectAgonistAtrial FibrillationAttenuatedAwarenessBasic ScienceBehaviorBindingBiological AssayBlood VesselsBrainBreathingCalcium ChannelCalmodulinCardiacCardiovascular systemCell NucleusCellsChemicalsCircadian RhythmsCoupledDihydropyridinesDoctor of PhilosophyDoseElectrophysiology (science)ElementsFeedbackFluorescence Resonance Energy TransferFunctional disorderGoalsHair CellsHandHeartIndividualKnowledgeL-Type Calcium ChannelsLaboratoriesLeadLibrariesLifeLocomotionMediatingMicroscopeMolecularMotorMuscle ContractionNeurodegenerative DisordersOutcomeParkinson DiseasePathologyPeriodicityPharmacologic SubstancePhysiologicalPhysiologyProtocols documentationPublished CommentReaderRecombinantsRegulationRoleSignal TransductionSkeletal MuscleSpeedSubstantia nigra structureSystemTestingTherapeuticToxic effectUrsidae Familybasecounterscreendihydropyridinefluorophoreimprovedinhibitor/antagonistneurotransmitter releasenovelnovel strategiespatch clamppositive moodresponseribbon synapsesmall moleculestable cell linetoolvoltage
中文摘要
描述(由申请人提供):CaV1.3通道是低阈值、二氢吡啶敏感的L型Ca 2+通道,介导全身的低电压信号和节律性。它们对于带状突触处的神经递质释放是必不可少的,例如在耳蜗毛细胞中发现的;它们介导心脏中的起搏;并且它们调节整个大脑中的振荡行为,例如在超交叉(昼夜节律起搏电路)和黑质(帕金森氏症中的原发性损伤部位)核中的重复爆发。因此,这些通道的过度活动可能会导致Ca 2+过载,从而诱发帕金森氏症,而这些通道的向下调节可能会增强积极的情绪和影响。显然,选择性抑制或增强CaV1.3通道而不是其他CaV 1 L型通道的小分子化合物对于CaV1.3作用的基础研究以及潜在地减轻许多CaV1.3相关的病理具有巨大的效用。然而,尽管已经发现了良好的L型通道拮抗剂和激动剂,但没有一种能够真正选择L型通道亚型。在这里,在寻找选择性调节剂,我们将利用一个独特的分子之间的相互作用ICDI和IQ域的CaV1.3通道,这种相互作用调制的强度Ca 2+反馈抑制(CDI)的这些通道。这一前景广阔的屏幕将根据三个具体目标进行起诉。1)使用包含350,000 - 500,00种化合物的MLSMR文库,对破坏或增强CaV1.3通道的IQ和ICDI结构域之间功能关键相互作用的小分子进行初步筛选。2)使用单个活细胞的基于显微镜的FRET分析来确认和鉴定来自目标1的候选命中。3)使用膜片钳电生理学测试用于调节CaV1.3 Ca 2+调节的候选化合物。总体而言,该项目有望成为CaV1.3与其他CaV 1 L型钙通道选择性调节剂的主要候选者。
英文摘要
DESCRIPTION (provided by applicant): CaV1.3 channels are low-threshold, dihydropyridine-sensitive L-type Ca2+ channels which mediate low-voltage signaling and rhythmicity throughout the body. They are essential for neurotransmitter release at ribbon synapses such as found in cochlear hair cells; they mediate pacemaking in the heart; and they modulate oscillatory behavior throughout the brain, such as the repetitive bursting in supra-chiasmatic (circadian pacemaking circuitry) and substantia nigra (locus of primary damage in Parkinson's) nuclei. As such, overactivity of these channels may predispose for Ca2+ overload precipitating Parkinson's, and downward modulation of these channels may enhance positive mood and affect. Clearly, small-molecule compounds that selectively inhibit or enhance CaV1.3 channels, rather than the other CaV1 L-type channels would be of enormous utility for basic studies of CaV1.3 roles, and for potentially amerliorating a number of CaV1.3-related pathologies. However, though excellent L-type channels antagonists and agonists have been discovered, none can truly select among the L-type channel subtypes. Here, in the search for selective modulators, we will exploit a unique molecular interaction between ICDI and IQ domains of CaV1.3 channels, where this interaction modulates the strength Ca2+ feedback inhibition (CDI) of these channels. This promising screen will be prosecuted according to three specific aims. 1) To perform a primary screen for small molecules that disrupt or enhance a functionally critical interaction between IQ and ICDI domains of CaV1.3 channels, using the MLSMR library of 350,000-500,00 compounds. 2) To confirm and identify candidate hits from Aim 1 using a microscope-based FRET analysis of single living cells. 3) To test candidate compounds for modulation of CaV1.3 Ca2+ regulation, using patch-clamp electrophysiology. Overall, this project promises lead candidates for selective modulators of CaV1.3 versus other CaV1 L-type calcium channels.
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会议论文
Chemical biological dissection of Ca2+ entry through Ca2+ channels
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批准号:8609908
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项目类别:
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资助金额:$35.44万
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财政年份:2013
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负责人:DAVID T YUE
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依托单位:
Modulators of CaV1.3 Ca2+ regulation
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批准号:8408867
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项目类别:
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资助金额:$4.05万
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财政年份:2012
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批准号:8417000
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项目类别:
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资助金额:$36.9万
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财政年份:2011
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负责人:DAVID T YUE
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依托单位:
Dynamic Calmodulin Regulation of Na Channels
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批准号:8087233
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项目类别:
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资助金额:$40.79万
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财政年份:2011
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依托单位:
Dynamic Calmodulin Regulation of Na Channels
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批准号:8217079
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项目类别:
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资助金额:$39.89万
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财政年份:2011
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负责人:DAVID T YUE
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依托单位:
Dynamic Calmodulin Regulation of Na Channels
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批准号:8604637
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项目类别:
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资助金额:$37.88万
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财政年份:2011
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负责人:DAVID T YUE
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依托单位:
Ca Regulation of Ca Channels
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批准号:8101126
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项目类别:
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资助金额:$34.5万
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财政年份:2007
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负责人:DAVID T YUE
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依托单位:
Ca Regulation of Ca Channels
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批准号:7886484
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项目类别:
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资助金额:$34.85万
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财政年份:2007
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负责人:DAVID T YUE
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依托单位:
Ca Regulation of Ca Channels
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批准号:7265541
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项目类别:
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资助金额:$34.85万
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财政年份:2007
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负责人:DAVID T YUE
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依托单位:
Ca Regulation of Ca Channels
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批准号:7649250
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项目类别:
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资助金额:$34.85万
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财政年份:2007
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负责人:DAVID T YUE
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依托单位:
Calmodulin/Ca channel physiology in heart
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批准号:6866486
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项目类别:
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资助金额:$40.88万
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财政年份:2004
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负责人:DAVID T YUE
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依托单位:
Calmodulin/Ca channel physiology in heart
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批准号:6767491
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项目类别:
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资助金额:$40.88万
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财政年份:2004
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负责人:DAVID T YUE
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依托单位:
Calmodulin/Ca channel physiology in heart
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批准号:7031630
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项目类别:
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资助金额:$39.91万
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财政年份:2004
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负责人:DAVID T YUE
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依托单位:
Calmodulin/Ca channel physiology in heart
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批准号:7393795
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项目类别:
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资助金额:$38.76万
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财政年份:2004
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负责人:DAVID T YUE
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依托单位:
Calmodulin/Ca channel physiology in heart
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批准号:7227160
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项目类别:
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资助金额:$38.76万
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财政年份:2004
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负责人:DAVID T YUE
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依托单位:
Calmodulin/Ca Channel Physiology in Heart
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批准号:8049724
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项目类别:
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资助金额:$42.75万
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财政年份:2004
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负责人:DAVID T YUE
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依托单位:
Calmodulin/Ca Channel Physiology in Heart
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批准号:8244473
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项目类别:
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资助金额:$42.53万
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财政年份:2004
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负责人:DAVID T YUE
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依托单位:
Calmodulin/Ca Channel Physiology in Heart
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批准号:8452681
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项目类别:
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资助金额:$40.16万
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财政年份:2004
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负责人:DAVID T YUE
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依托单位:
Calmodulin/Ca Channel Physiology in Heart
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批准号:7590763
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项目类别:
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资助金额:$42.78万
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财政年份:2004
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负责人:DAVID T YUE
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依托单位:
Ca2+ Regulation of Ca Channels
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批准号:6915097
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项目类别:
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资助金额:$36.79万
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财政年份:2002
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负责人:DAVID T YUE
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依托单位:
海外基金