Nucleation and dynamics of exocytotic fusion pores
胞吐融合孔的成核和动力学
基本信息
- 批准号:10376228
- 负责人:
- 金额:$ 36.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-02-15 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAffinityArtificial MembranesBindingBiochemicalBiological AssayCalciumCell fusionCell membraneCellsChargeCommunicationComplexCoupledDependenceDockingElectrophysiology (science)EndocrineEndocytosisEngineeringEventEvolutionExocytosisFluorescence MicroscopyHealthHormonesHumanIndividualIonsKineticsLipidsMediatingMembraneMembrane FusionMembrane ProteinsMethodsMolecularMonitorNeuroendocrine CellNeuronsNeurotransmittersPhasePhysiologicalProbabilityProcessPropertyProtein IsoformsProteinsRecyclingRegulationResolutionRoleSNAP receptorSecretory VesiclesShapesSpeedSynaptic CleftSynaptic VesiclesSystemTechnologyTestingTimeVesiclecell typeexperienceexperimental studyflash photolysismicrodevicenanodiskneurotransmitter releaseparticlereconstitutionresponsesensorsynaptotagmin Itarget SNARE proteinsultravioletvesicular SNARE proteins
项目摘要
PROJECT SUMMARY:
In neurons, synaptic vesicles (SV) packaged with neurotransmitter fuse with the plasma membrane to release
their content that is sensed across the synaptic cleft. Release is triggered by a local increase in the calcium
concentration following depolarization. Release kinetics comprise a synchronous phase (0.1-5 ms after calcium
elevation), and a much slower asynchronous phase (~100 ms). How membrane fusion can be triggered so
rapidly and how the kinetics are regulated are not well understood. Hormones are released in a similar fashion,
with multiple kinetic phases, using some of the same protein machinery, via fusion of hormone containing
secretory granules (SG) with the plasma membrane. The initial ~1-3 nm wide connection between the fusing
compartments, called the fusion pore, can flicker open-closed in succession before either closing permanently
(transient fusion) or dilating fully. There is large variability between cell types (pore open times span ~100 µs
to 10s of s) and within the same cell (some pores flicker, some dilate abruptly). Pore flickering is modulated by
physiological inputs such as stimulation strength, with important consequences about what is released (only
small cargo can escape through a small pore), on what time course, and how exocytosis is coupled to
endocytosis. Despite the importance of fusion pores in regulating release, very little is understood regarding
mechanisms controlling pore nucleation and dynamics. This is mainly due to difficulties in studying fusion
pores in reconstituted systems with well-defined protein and membrane components that would allow isolating
the role of each. Fusion mediated by exocytic SNARE proteins and their regulators has been reconstituted and
studied for the past 20 years. However, methods that can monitor single reconstituted fusion pores with sub-
ms resolution have been lacking. During the last cycle, we developed such methods for the first time, and
explored mechanisms regulating fusion pores induced by SNAREs alone. In the next cycle, we propose to use
those methods to (1) define the role of SNARE-interacting proteins in nucleation and dynamics of
fusion pores and the selectivity of small pores. To characterize how the calcium sensors for exocytosis
and other essential components of the release machinery contribute to fusion pore properties, we will use
electrophysiology, nanodiscs, engineered cells, single-particle fluorescence microscopy, microfabricated
devices, and artificial bilayers. We will also characterize selectivity of small fusion pores for ions, which is
highly relevant for determining what is released during transient fusion events. We will then (2) dissect
mechanisms contributing to kinetics of calcium-triggered exocytosis. The approaches will be
augmented to allow rapid (~1 ms) [Ca2+] elevation using microperfusion or ultraviolet flash photolysis. These
will enable defining how different sensors and release complexes regulate release kinetics and what determines
the high calcium-cooperativity of release. These fundamental studies will advance our understanding of how
neurotransmitter and hormone release are regulated, with potential impact on human health in the long term.
项目总结:
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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ERDEM KARATEKIN其他文献
ERDEM KARATEKIN的其他文献
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{{ truncateString('ERDEM KARATEKIN', 18)}}的其他基金
Self-assembled DNA elastic networks for measuring membrane tension in live cells
用于测量活细胞膜张力的自组装 DNA 弹性网络
- 批准号:
10196486 - 财政年份:2021
- 资助金额:
$ 36.64万 - 项目类别:
Self-assembled DNA elastic networks for measuring membrane tension in live cells
用于测量活细胞膜张力的自组装 DNA 弹性网络
- 批准号:
10405097 - 财政年份:2021
- 资助金额:
$ 36.64万 - 项目类别:
Dynamics of membrane tension and synaptic vesicle recycling
膜张力和突触小泡回收的动力学
- 批准号:
10364698 - 财政年份:2021
- 资助金额:
$ 36.64万 - 项目类别:
Dynamics of membrane tension and synaptic vesicle recycling
膜张力和突触小泡回收的动力学
- 批准号:
10594954 - 财政年份:2021
- 资助金额:
$ 36.64万 - 项目类别:
Mechanisms of the calcium-triggered neurotransmitter release machinery in hair cells
毛细胞中钙触发神经递质释放机制的机制
- 批准号:
10424526 - 财政年份:2020
- 资助金额:
$ 36.64万 - 项目类别:
Mechanisms of the calcium-triggered neurotransmitter release machinery in hair cells
毛细胞中钙触发神经递质释放机制的机制
- 批准号:
10197098 - 财政年份:2020
- 资助金额:
$ 36.64万 - 项目类别:
Mechanisms of the calcium-triggered neurotransmitter release machinery in hair cells
毛细胞中钙触发神经递质释放机制的机制
- 批准号:
10636938 - 财政年份:2020
- 资助金额:
$ 36.64万 - 项目类别:
Dynamics of membrane tension and synaptic vesicle recycling
膜张力和突触小泡回收的动力学
- 批准号:
9808543 - 财政年份:2019
- 资助金额:
$ 36.64万 - 项目类别:
Nucleation and dynamics of exocytotic fusion pores
胞吐融合孔的成核和动力学
- 批准号:
8615066 - 财政年份:2014
- 资助金额:
$ 36.64万 - 项目类别:
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