Polarized Trafficking of K+ Channels in the Kidney
肾脏 K 通道的极化运输
基本信息
- 批准号:7171560
- 负责人:
- 金额:$ 33.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-01-01 至 2008-02-29
- 项目状态:已结题
- 来源:
- 关键词:Candidate Disease GeneCell membraneCellsCellular biologyClathrinComplexDataDiseaseDuct (organ) structureElectrophysiology (science)EndocytosisHealthHomeostasisIon ChannelKidneyKnockout MiceMembraneMembrane ProteinsMolecularMolecular GeneticsPDZ proteinPathway interactionsPhysiologicalPotassiumPotassium ChannelPrincipal InvestigatorProcessProtein SortingsRateRegulationRoleSignal TransductionSorting - Cell MovementSpecific qualifier valueSurfaceTestingTranscription Factor AP-2 AlphaTransgenic OrganismsWorkbasebasolateral membranedesigninsightinterdisciplinary approachinward rectifier potassium channelmutantnovelprogramsprotein protein interactionscaffoldsecretion processtrafficking
项目摘要
Polarized trafficking, appropriate surface expression and disparate regulation of at least two different potassium
channels on opposite membrane domains of the renal cortical collecting duct (CCD) principal cell insure an efficient
potassium secretion process and potassium homeostasis. Here, we propose to elucidate the molecular mechanisms
governing polarized targeting and surface expression of the basolateral CCD channel, Kir 2.3. Our previous work
suggests a hierarchical trafficking program, involving a novel biosynthetic sorting process and dynamic, PDZ-
dependent retention at the basolateral membrane. To critically test this hypothesis, a stepwise multidisciplinary
approach, combining molecular genetics, cellular biology, electrophysiology and transgenics, will be employed to
answer the following questions: 1. How is the basolateral trafficking signal in Kit 2.3 interpreted within the
biosynthetic sorting pathway? This aim is designed to critically test the role of novel biosynthetic sorting machinery
candidates. 2. Does internalization of Kit 2.3 occur via clathrin-dependent mechanism, involving a direct
interaction with the # subnnit of AP2 adaptor complex. This aim is designed to elucidate the molecular mechanisms
involved in endocytotic trafficking of Kit 2.3, providing a context to understand how PDZ interactions regulate Kit 2.3
expression. 3. Does interaction with the Lin-7/CASK PDZ complex coordinate basolateral expression of Kit 2.3
by limiting endosomal trafficking. In this aim, plasma membrane turnover rate and intracellular trafficking of
externally tagged channels will be assessed in the absence and presence of dominant interfering Lin-7 constructs. 4.
How is interaction with MOPP, a unique PDZ protein, regulated to control surface expression of Kir 2.3? This
aim is designed to test the hypothesis that MOPP acts as a natural negative regulator of Lin 7 PDZ scaffolding-
complexes. 5. Does Lin-7 interaction regulate Kir 2.3 expression in the CCD during potassium adaptation? In this
aim, we will determine if Lin -7 interaction underpins the physiological regulation of Kir 2.3. Wild-type and Lin-7
knockout mice will be studied. These studies represent a timely and important extension of the principal investigator's
work, and should ultimately provide considerable insight into the basis of renal K handling and K homeostasis in health
and disease while illuminating new and presently unexplored mechanisms controlling membrane-protein sorting in the
kidney.
极化运输,适当的表面表达和至少两种不同钾离子的不同调节
肾皮质集合管(CCD)主细胞相对膜域上的通道确保了有效的
钾分泌过程和钾稳态。在这里,我们建议阐明分子机制
控制基底外侧CCD通道的极化靶向和表面表达,Kir 2.3。我们以前的工作
提出了一个层次贩运计划,涉及一种新的生物合成分选过程和动态,PDZ-
基底外侧膜的依赖性保留。为了严格检验这一假设,一个逐步的多学科
结合分子遗传学、细胞生物学、电生理学和转基因学的方法,
回答以下问题:1.如何解释试剂盒2.3中的基底外侧运输信号,
生物合成分选途径这一目标旨在严格测试新型生物合成分选机械的作用
候选人2. Kit 2.3的内化是否通过网格蛋白依赖性机制发生,涉及直接的
与AP 2衔接子复合物的#亚单位的相互作用。这一目标旨在阐明分子机制
参与Kit 2.3的内吞运输,为理解PDZ相互作用如何调节Kit 2.3提供了背景
表情3.与Lin-7/CASK PDZ复合物的相互作用是否协调Kit 2.3的基底外侧表达
通过限制内体运输。在这个目标中,质膜周转率和细胞内运输的
在不存在和存在显性干扰Lin-7构建体的情况下评估外部标记的通道。4.
如何与MOPP(一种独特的PDZ蛋白)相互作用以控制Kir 2.3的表面表达?这
目的是检验MOPP作为Lin 7 PDZ支架的天然负调节剂的假设-
配合物5. Lin-7相互作用是否调节钾适应过程中CCD中Kir 2.3的表达?在这
目的,我们将确定Lin-7相互作用是否支持Kir 2.3的生理调节。野生型和Lin-7
将研究敲除小鼠。这些研究代表了主要研究者的及时和重要的扩展,
工作,并最终提供相当深入的基础上,肾钾处理和钾稳态的健康
和疾病,同时阐明了新的和目前尚未探索的机制,控制膜蛋白分选,
肾
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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Paul A Welling其他文献
Paul A Welling的其他文献
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{{ truncateString('Paul A Welling', 18)}}的其他基金
Polarized Trafficking of K+ Channels in the Kidney
肾脏 K 通道的极化运输
- 批准号:
7913908 - 财政年份:2009
- 资助金额:
$ 33.09万 - 项目类别:
Multigene Kinase Network, Kidney Transport and Salt in Essential Hypertension
原发性高血压中的多基因激酶网络、肾脏转运和盐
- 批准号:
7938618 - 财政年份:2009
- 资助金额:
$ 33.09万 - 项目类别:
Multigene Kinase Network, Kidney Transport and Salt in Essential Hypertension
原发性高血压中的多基因激酶网络、肾脏转运和盐
- 批准号:
7820603 - 财政年份:2009
- 资助金额:
$ 33.09万 - 项目类别:
Molecular Basis of Potassium Channels in the Kidney
肾脏钾通道的分子基础
- 批准号:
8438676 - 财政年份:2003
- 资助金额:
$ 33.09万 - 项目类别:
Molecular Basis of Potassium Channels in the Kidney
肾脏钾通道的分子基础
- 批准号:
8882403 - 财政年份:2003
- 资助金额:
$ 33.09万 - 项目类别:
Polarized Trafficking of K+ Channels in the Kidney
肾脏 K 通道的极化运输
- 批准号:
6835681 - 财政年份:2003
- 资助金额:
$ 33.09万 - 项目类别:
Polarized Trafficking of K+ Channels in the Kidney
肾脏 K 通道的极化运输
- 批准号:
6693785 - 财政年份:2003
- 资助金额:
$ 33.09万 - 项目类别:
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