Regulation of inositol trisphosphate receptors
肌醇三磷酸受体的调节
基本信息
- 批准号:10326833
- 负责人:
- 金额:$ 32.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAdenine NucleotidesAgonistAmoeba genusAnimal ModelBindingBinding SitesBioenergeticsBiologicalC-terminalCRISPR/Cas technologyCalciumCalcium SignalingCarbonCell CycleCell DeathCell LineCell divisionCell membraneCell physiologyCellsCervix carcinomaChargeChemicalsChickensCitric Acid CycleClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsCryoelectron MicroscopyD CellsDermalDiabetes MellitusDiseaseDrug or chemical Tissue DistributionEndoplasmic ReticulumEnergy SupplyEnzymesExocytosisFRAP1 geneFamilyFeedbackFertilizationFibroblastsFrequenciesGene ExpressionGeneticGenetic TranscriptionGlucoseGlutamineGlycolysisGoalsGrowthGrowth FactorHeart DiseasesHela CellsHepatocyteHereditary DiseaseHomoHormonesHuman Cell LineITPR1 geneInositolInterruptionKnock-outKnockout MiceLigand Binding DomainLigandsLocationMalate-Aspartate Shuttle PathwayMalignant Epithelial CellMalignant NeoplasmsMalignant neoplasm of cervix uteriMass Spectrum AnalysisMeasuresMediatingMemoryMetabolicMetabolismMitochondriaMolecularMolecular ConformationMonitorMuscle ContractionMutagenesisMutateMutationN-terminalNADHNeurodegenerative DisordersNeurotransmittersNormal CellOxidoreductaseOxygen ConsumptionPatientsPeriodicityPhasePhosphorylationPhosphotransferasesProcessProductionPropertyProtein IsoformsProtein KinaseProteinsRegulationRespiratory ChainRoleSignal TransductionSiteStagingStructureTechnologyTestingTherapeuticTracerTransfectionTransmembrane DomainWorkbasebiological researchcancer cellcell motilitycell transformationcrosslinkdesignexperimental studyextracellularreceptorresponsetranscription factor
项目摘要
Calcium is a universal messenger controlling a multitude of cellular responses including muscle contraction,
exocytosis, memory, fertilization, metabolism, proliferation and cell death. Numerous hormones,
neurotransmitters and growth factors stimulate the formation of inositol 1,4,5-trisphosphate ( IP3 ) which acts
on a family of receptors ( IP3Rs ) located in the endoplasmic reticulum that function as ligand-gated Ca2+
channels. The depletion of intracellular Ca2+ stores also activates Ca2+ influx mechanisms in the plasma
membrane. Thus, the interaction of IP3 with its receptor activates all phases of a Ca2+ signal. IP3Rs are
regulated by Ca2+ and phosphorylation but the molecular basis of this regulation is poorly understood. Ca2+
released from IP3Rs is locally transmitted to the mitochondria and can stimulate metabolism, and in higher
amounts, can also initiate cell death. Cancer cells have been proposed to be highly dependent on IP3R-
mediated mitochondrial Ca2+ transfer for their survival. The advent of CRISPR/Cas-9 technology has allowed
the genetic ablation of all three IP3R isoforms from HEK293 and HeLa cervix carcinoma cells. The proposal is
centered on the use of these cell lines to a) study the adaptive mechanisms allowing the cells to survive in the
complete absence of Ca2+ signaling and b) to take advantage of a null background for structure-function
studies exploring the molecular mechanism by which IP3 opens the channel and the mechanism of feed-back
regulation by Ca2+. The two specific aims are: 1] Characterize adaptive mechanisms in IP3R-3KO cells: The
impact of a lack of Ca2+ regulation of metabolism will be investigated by measuring several bioenergetic
parameters and 13C-tracer metabolism. Proliferation, cell-cycle status, cell death and transcriptional rewiring
will be explored. 2A] How does IP3 open the channel? Chemical crosslinking/mass spectroscopy will be used
to validate cryo-EM structures and monitor conformational changes mediated by IP3 in native IP3Rs.
Mutagenesis of key residues will be used to test proposed allosteric mechanisms of gating. 2B] Identification
of the Ca2+ regulatory sites in IP3Rs: Based on the most recent cryo-EM structures of IP3R1 and IP3R3 we
have identified 3 clusters of negatively charged residues that are candidates for Ca2+ regulatory sites. Their
functional role as stimulatory or inhibitory sites will be assessed by mutagenesis. The role of these sites will
also be tested by mutagenesis of the Ca2+-insensitive IP3R from Capsaspora owczarzaki . The long-term goal
of the proposal is to better understand the role of Ca2+signaling in normal cells, cancer cells and in inherited
disorders inactivating IP3R function. The study should also provide fundamental mechanistic information on
how these important channels work and are regulated.
钙是一种控制多种细胞反应的通用信使,包括肌肉收缩,
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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SURESH K JOSEPH其他文献
SURESH K JOSEPH的其他文献
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{{ truncateString('SURESH K JOSEPH', 18)}}的其他基金
IP3 Receptor Phosphorylation by Akt Kinase
Akt 激酶对 IP3 受体进行磷酸化
- 批准号:
6913966 - 财政年份:2005
- 资助金额:
$ 32.18万 - 项目类别:
IP3 Receptor Phosphorylation by Akt Kinase
Akt 激酶对 IP3 受体进行磷酸化
- 批准号:
7016345 - 财政年份:2005
- 资助金额:
$ 32.18万 - 项目类别:
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