Molecular understanding of membrane sensors
膜传感器的分子理解
基本信息
- 批准号:10374045
- 负责人:
- 金额:$ 79.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2023-09-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAddressAnionsArchitectureBiochemicalBiological ModelsBiologyBiosensorBladderBlood PressureBlood VesselsCell VolumesCell membraneCell physiologyCellsCellular Metabolic ProcessCellular MorphologyCerebral IschemiaCerebral Ischemia-HypoxiaChloridesClassificationClustered Regularly Interspaced Short Palindromic RepeatsComplexCongestive Heart FailureCoupledCryoelectron MicroscopyData SetDetergentsDiseaseEnvironmentErythrocytesFaceFamily memberHearingHomeostasisHomoHomologous GeneHydrophobicityHyponatremiaIntegral Membrane ProteinIon ChannelIon Channel GatingIonic StrengthsIonsKnock-outKnowledgeLigandsLipid BilayersLipidsLungMechanicsMembraneModelingMolecularMolecular ConformationMusMutagenesisMutationOsmolar ConcentrationOsmotic PressureOsmotic ShocksPainPhysiologicalPiezo 1 ion channelPiezo 2 ion channelPliabilityPopulationPreparationPropertyProprioceptionProteinsRegulationResolutionRespiratory physiologyRoleSamplingShapesStimulusStressStrokeStructureStructure-Activity RelationshipSwellingSystemTestingTouch sensationTraumaVesiclebasebody systemdisease-causing mutationdrinking waterenvironmental stressorexperimental studyextracellularinsightmechanical forcemolecular modelingmutantnanodiskpressureresponsesensorstoichiometrysuccess
项目摘要
Project Summary/Abstract
Integral membrane proteins act as critical sensors that respond to intra- and extra-cellular stimuli. These
proteins are involved in many homeostatic cellular functions such as tension/mechanosensation and
osmosensation, and mutations in these sensors can cause pathophysiological states. In this proposal, we will
study the structure and function of the mechanosensitive ion channel, Piezo1, and the osmotic sensing volume-
regulated anion channels (VRACs). Both channels were recently identified in one of the co-PI’s lab and are active
targets for structural studies. Mechanically activated ion channels are thought to be responsible for hearing,
sensing touch/pain, but also sensing arterial blood pressure, and lung and bladder inflation. Piezos are
mechanosensitive ion channels essential for touch, proprioception, vascular biology, red blood cell morphology,
and respiratory physiology. Piezo1 senses mechanical force in lipid bilayers; however, how membrane tension
is sensed by these proteins and transmitted into ion channel gating is not known. Recently, we and others have
solved <4Å resolution structures of Piezo1, however in all structures key portions of Piezo1 were not well
resolved, hindering mechanistic understanding of how mechanosensation and ion channel activity are coupled.
We propose several approaches to build off our initial success and using new structures test hypotheses to
address the remaining structural and mechanistic questions about Piezo1.
The cellular response to osmotic pressures beyond the homeostatic range is critical for survival and yet
significantly contributes to damage caused by cerebral ischemia, stroke, trauma, and hyponatremia . Cell swelling
caused by hypo-osmotic stress activates ion channels including volume-regulated anion channels (VRAC).
VRAC is a diverse set of heteromeric channels of undefined complexity composed of the essential LRRC8A
(“SWELL1”) subunit and any of 4 other LRRC8 family members. Despite recent high-resolution structures of
homo-hexameric LRRC8A from our group and others, the number of subunits, exact composition and
stoichiometry of VRAC are still unknown. Heterologous expression has revealed that important differential
physiological functions of VRAC are dependent on the identity of associating subunits. The primary focus of our
proposed studies is the elucidation of the structure and subunit arrangement of VRACs using high-resolution
cryo-electron microscopy (cryo-EM), and how each of the various assemblies accomplishes different functions.
We believe this proposal targeting these important ion channels will significantly impact our knowledge of
cell volume homeostasis in response to environmental stresses, as well as cell response to membrane tension,
impinging on all vertebrate organ systems since Piezos and VRACs are nearly ubiquitous.
项目总结/摘要
整合膜蛋白充当对细胞内和细胞外刺激做出反应的关键传感器。这些
蛋白质参与许多稳态细胞功能,例如张力/机械感觉,
这些传感器的突变可能导致病理生理状态。在本提案中,我们将
研究机械敏感离子通道Piezo 1的结构和功能,以及渗透敏感体积-
调节阴离子通道(VRAC)。这两个通道最近在一个合作PI的实验室中被发现,并且是活跃的
结构研究的目标。机械激活的离子通道被认为是负责听力,
感测触摸/疼痛,而且还感测动脉血压以及肺和膀胱充气。Piezos是
机械敏感离子通道对于触觉、本体感觉、血管生物学、红细胞形态学,
和呼吸生理学。Piezo 1传感脂质双层中的机械力;然而,膜张力如何
被这些蛋白质感知并被传输到离子通道门控中是未知的。最近,我们和其他人
Piezo 1的结构解析度<4 × 10 - 5,但在所有结构中,Piezo 1的关键部分解析度不高
解决,阻碍机械感觉和离子通道活动如何耦合的机械理解。
我们提出了几种方法来建立我们的初步成功,并使用新的结构测试假设,
解决有关Piezo 1的剩余结构和机械问题。
细胞对超出稳态范围的渗透压的反应对生存至关重要,
显著促进由脑缺血、中风、创伤和低钠血症引起的损伤。细胞肿胀
由低渗透压应激引起的低渗透压激活离子通道,包括体积调节阴离子通道(VRAC)。
VRAC是由必需的LRRC 8A组成的一组复杂性不确定的异聚体通道
(“SWELL 1”)亚基和4个其他LRRC 8家族成员中的任一个。尽管最近的高分辨率结构,
同源六聚体LRRC 8A从我们的小组和其他人,亚基的数量,确切的组成和
VRAC化学计量仍然未知。异源表达揭示了重要的差异表达,
VRAC的生理功能取决于相关亚基的身份。我们的主要重点是
建议的研究是使用高分辨率的VRAC的结构和亚基排列的阐明
冷冻电子显微镜(cryo-EM),以及各个组件如何实现不同的功能。
我们相信,针对这些重要离子通道的这一提议将显著影响我们对
响应于环境压力的细胞体积稳态,以及响应于膜张力的细胞,
由于压电和VRAC几乎无处不在,因此它们会影响所有脊椎动物的器官系统。
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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Ardem Patapoutian其他文献
Ardem Patapoutian的其他文献
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{{ truncateString('Ardem Patapoutian', 18)}}的其他基金
The Role of Sensory Neurons Innervating Internal Organs
感觉神经元支配内脏器官的作用
- 批准号:
10504106 - 财政年份:2022
- 资助金额:
$ 79.36万 - 项目类别:
The Role of Sensory Neurons Innervating Internal Organs
感觉神经元支配内脏器官的作用
- 批准号:
10685444 - 财政年份:2022
- 资助金额:
$ 79.36万 - 项目类别:
Mechanisms of force sensing in the nervous system
神经系统中的力传感机制
- 批准号:
10524765 - 财政年份:2017
- 资助金额:
$ 79.36万 - 项目类别:
Mechanisms of force sensing in the nervous system
神经系统中的力传感机制
- 批准号:
10055966 - 财政年份:2017
- 资助金额:
$ 79.36万 - 项目类别:
Mechanisms of force sensing in the nervous system
神经系统中的力传感机制
- 批准号:
10308074 - 财政年份:2017
- 资助金额:
$ 79.36万 - 项目类别:
Mechanisms of force sensing in the nervous system
神经系统中的力传感机制
- 批准号:
10748552 - 财政年份:2017
- 资助金额:
$ 79.36万 - 项目类别:
Role of mechanically activated ion channels in somatosensation
机械激活离子通道在体感中的作用
- 批准号:
8508241 - 财政年份:2012
- 资助金额:
$ 79.36万 - 项目类别:
Role of mechanically activated ion channels in somatosensation
机械激活离子通道在体感中的作用
- 批准号:
9982299 - 财政年份:2012
- 资助金额:
$ 79.36万 - 项目类别:
Structure Function of Mechanically Activated Ion Channel
机械激活离子通道的结构功能
- 批准号:
8681567 - 财政年份:2012
- 资助金额:
$ 79.36万 - 项目类别:
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