Allosteric ENaC Regulation
变构 ENaC 调节
基本信息
- 批准号:8628315
- 负责人:
- 金额:$ 33.33万
- 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:2014-02-10 至 2019-01-31
- 项目状态:已结题
- 来源:
- 关键词:ASIC channelAcidic RegionAddressAffectAldosteroneApicalBindingBinding SitesBlood PressureC-terminalCell surfaceChemicalsCleaved cellCuesDataDistalElectrostaticsEnvironmentEpithelialExtracellular DomainExtracellular FluidFamilyFamily memberFingersGene FamilyGoalsGray unit of radiation doseHealthHumanIon ChannelKidneyLigand BindingLigandsLocationMechanical StressMembraneModelingMolecularMolecular ConformationMolecular StructureNa(+)-K(+)-Exchanging ATPaseNephronsPeptide HydrolasesPeptidesPlayProcessProteolysisProtonsRecruitment ActivityRegulationReportingRoleSiteSodiumSodium ChannelSodium ChlorideStructural ModelsStructureSurfaceTaste PerceptionTestingThumb structureTongueWorkWristapical membranebaseblood pressure regulationcrosslinkdesignepithelial Na+ channelextracellularmemberpredictive modelingpublic health relevanceresearch studyshear stress
项目摘要
The epithelial Na+ channel (ENaC) has a key role in the regulation of extracellular fluid volume and blood
pressure. ENaC belongs to a family of ion channels that sense the external environment and it responds to
several environmental cues including Na+, Cl-, protons, proteases and shear stress. How these channels
respond to these extracellular cues is poorly understood. The goal of this proposal is to determine the
molecular mechanisms of ENaC regulation by external Na+ and proteases. They combine to create specific
pools of channels that are constitutively active, and others that are recruited only when extracellular Na+
concentrations are low. The proposed studies based on structural models will determine molecular
mechanisms of regulation by both factors. Binding sites for Na+ and an inhibitory peptide will be defined, as
well as dynamic changes induced upon binding of Na+ or an inhibitory peptide. Experiments will test whether
an acidic pocket hosts a Na+ inhibitory binding site, and a region adjacent to the acidic pocket hosts the binding
site for an inhibitory peptide. For either effector to induce changes in channel activity, they must induce local
conformational changes upon binding that propagate to the channel pore. Experiments are proposed to trap
functional conformations of the channel using chemical crosslinks and electrostatic effects. A mechanistic
understanding of how extracellular factors regulate ENaC will inform our understanding of ENaC functional
regulation and how related channels may sense their environments.
上皮Na+通道(ENaC)在细胞外液容量和血液的调节中具有关键作用
压力ENaC属于离子通道家族,其感测外部环境,并且其响应于
几种环境线索,包括Na+,Cl-,质子,蛋白酶和剪切应力。这些渠道如何
对这些细胞外信号的反应知之甚少。本提案的目的是确定
通过外部Na+和蛋白酶调节ENaC的分子机制。它们联合收割机
组成性激活的通道池,以及仅在细胞外Na+
浓度很低。基于结构模型的拟议研究将确定分子
这两种因素的调节机制。Na+和抑制肽的结合位点将定义为:
以及在结合Na+或抑制肽时诱导的动态变化。实验将检验
酸性口袋容纳Na+抑制结合位点,并且与酸性口袋相邻的区域容纳结合位点。
抑制肽的位点。对于任一效应物诱导通道活性的变化,它们必须诱导局部
结合后的构象变化传播到通道孔。实验旨在捕获
使用化学交联和静电效应的通道的功能构象。一种机械的
了解细胞外因子如何调节ENaC将有助于我们了解ENaC的功能
监管以及相关通道如何感知其环境。
项目成果
期刊论文数量(0)
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{{ truncateString('OSSAMA B KASHLAN', 18)}}的其他基金
Organization and Structure of ENaC Transmembrane Segments
ENaC 跨膜片段的组织和结构
- 批准号:
7994908 - 财政年份:2009
- 资助金额:
$ 33.33万 - 项目类别:
Organization and Structure of ENaC Transmembrane Segments
ENaC 跨膜片段的组织和结构
- 批准号:
7469770 - 财政年份:2008
- 资助金额:
$ 33.33万 - 项目类别:
Organization and Structure of ENaC Transmembrane Segments
ENaC 跨膜片段的组织和结构
- 批准号:
7578920 - 财政年份:2008
- 资助金额:
$ 33.33万 - 项目类别:
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