Molecular and cellular mechanisms of store-operated calcium channels
钙池操纵的钙通道的分子和细胞机制
基本信息
- 批准号:10623620
- 负责人:
- 金额:$ 55.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-01 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:AppearanceAutoimmune DiseasesBindingBiological AssayCalciumCalcium ChannelCalcium SignalingCell membraneCell physiologyCellsComplexDiffusionDiseaseExcisionFluorescenceGoalsHumanImmunityImmunologic Deficiency SyndromesIndividualIon ChannelLaboratoriesLeadLocationMolecularMolecular ConformationMonitorMuscleMutationPathway interactionsPhysiological ProcessesPositioning AttributeProcessPropertyProteinsRegulationRoleSTIM1 geneSignal TransductionSiteTechniquescell motilitycostcrosslinkdrug developmentgain of functionhuman diseaseimmune activationloss of function mutationnew therapeutic targetorgan transplant rejectionpreventreceptorsingle moleculestoichiometry
项目摘要
Store-operated Ca2+ entry (SOCE) generates Ca2+ signals that are critical for many physiological processes,
from immune cell activation and differentiation to muscle activity, secretion, and motility. Store-operated Ca2+
channels (SOCs) are activated by receptors that deplete Ca2+ from the ER; the loss of Ca2+ is sensed by STIM1,
which then accumulates at ER-plasma membrane (ER-PM) junctions where it binds, traps, and activates
calcium-selective Orai channels diffusing in the PM. Gain-of-function and loss-of-function mutations in this
pathway have both been connected to serious human diseases, underscoring the critical importance of precise
regulation. The long-term goal of our laboratory is to understand the molecular basis of SOC properties and
regulation as well as their cellular roles. While the overall organization of the SOCE pathway is now known and
many of the underlying proteins have been identified, major gaps still exist in our understanding of how they act
to regulate SOCE location and amplitude. Over the next five years we aim to investigate three fundamental
processes that regulate calcium influx through SOCs. (1) The dynamics of ER-PM junctions. These junctions
where the ER closely approaches the PM are the only sites in the cell where STIM can bind and activate Orai,
such that their size, abundance and location determine both the amplitude and location of Ca2+ entry. While a
host of tethering proteins at junctional sites is known, their specific roles in junction initiation vs. turnover is
unclear. By monitoring the appearance and removal of ER-PM junctions in living cells with fluorescent markers
we will distinguish the different contributions of known tethering proteins to the initiation, lifetime and turnover
rate of new junctions, as well as their ability to conduct SOCE. (2) The mechanism of STIM1 activation and its
interaction with Orai1. The cytosolic domain of STIM1 undergoes a massive conformational change after ER
Ca2+ depletion in order to unmask and extend the CRAC activation domain (CAD) to activate Orai in the plasma
membrane. By studying STIM1 with single-molecule fluorescence and crosslinking techniques we aim to identify
steps in the activation process and intermediate states that may help mitigate the energetic cost of unfolding and
refolding STIM1. Similar approaches will be applied to determine basic features of the STIM-Orai interaction -
the stoichiometry of the STIM-Orai complex, the conformation of CAD in the bound state, and the binding
interface itself – which are currently not understood. (3) A molecular mechanism for Ca2+-dependent inactivation
(CDI). Despite progress in identifying multiple residues and domains in STIM and Orai that are critical for CDI,
an integrated mechanism is still lacking. We will use a pore accessibility assay to localize the position of the
inactivation gate, and explore functional and physical interactions of CDI domains to understand how they
cooperate to bring about CDI. Overall, the results of our studies will reveal fundamental cellular and molecular
mechanisms that control the strength of store-operated calcium signals in diverse cells, and may suggest new
strategies for regulating them to explore cellular functions and develop new treatments for human disease.
存储操作Ca2+入口(SOCE)产生Ca2+信号,这对许多生理过程至关重要,
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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RICHARD S LEWIS其他文献
RICHARD S LEWIS的其他文献
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{{ truncateString('RICHARD S LEWIS', 18)}}的其他基金
ION CHANNELS AND SIGNALING MECHANISMS IN T LYMPHOCYTES
T 淋巴细胞中的离子通道和信号传导机制
- 批准号:
6018824 - 财政年份:1991
- 资助金额:
$ 55.55万 - 项目类别:
ION CHANNELS AND SIGNALING MECHANISMS IN T LYMPHOCYTES
T 淋巴细胞中的离子通道和信号传导机制
- 批准号:
2183119 - 财政年份:1991
- 资助金额:
$ 55.55万 - 项目类别:
ION CHANNELS AND SIGNALING MECHANISMS IN T LYMPHOCYTES
T 淋巴细胞中的离子通道和信号传导机制
- 批准号:
6386034 - 财政年份:1991
- 资助金额:
$ 55.55万 - 项目类别:
ION CHANNELS AND SIGNALING MECHANISMS IN T LYMPHOCYTES
T 淋巴细胞中的离子通道和信号传导机制
- 批准号:
2444775 - 财政年份:1991
- 资助金额:
$ 55.55万 - 项目类别:
Ion Channels and Signaling Mechanisms in T Lymphocytes
T 淋巴细胞中的离子通道和信号传导机制
- 批准号:
9238964 - 财政年份:1991
- 资助金额:
$ 55.55万 - 项目类别:
Ion Channels and Signaling Mechanisms in T Lymphocytes
T 淋巴细胞中的离子通道和信号传导机制
- 批准号:
8686868 - 财政年份:1991
- 资助金额:
$ 55.55万 - 项目类别:
Ion Channels and Signaling Mechanisms in T Lymphocytes
T 淋巴细胞中的离子通道和信号传导机制
- 批准号:
8854089 - 财政年份:1991
- 资助金额:
$ 55.55万 - 项目类别:
ION CHANNELS AND SIGNALING MECHANISMS IN T LYMPHOCYTES
T 淋巴细胞中的离子通道和信号传导机制
- 批准号:
3304830 - 财政年份:1991
- 资助金额:
$ 55.55万 - 项目类别:
Ion Channels and Signaling Mechanisms In T Lymphocytes
T 淋巴细胞中的离子通道和信号传导机制
- 批准号:
6825865 - 财政年份:1991
- 资助金额:
$ 55.55万 - 项目类别:
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