Gating Mechanisms of KCNQ1/IKS Channels
KCNQ1/IKS 通道的门控机制
基本信息
- 批准号:10491284
- 负责人:
- 金额:$ 62.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-20 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:Action PotentialsAnti-Arrhythmia AgentsArrhythmiaBindingBinding SitesCalmodulinCardiacCardiac Electrophysiologic TechniquesCartoonsCell LineCellsComplexCouplingCryoelectron MicroscopyDataDevelopmentElectrophysiology (science)Family memberFluorescence Resonance Energy TransferFluorescence SpectroscopyGoalsHeartHumanInterruptionLeadLeftLobeMammalian CellMediatingMembraneMembrane LipidsMolecularMolecular ConformationMotionMutagenesisMutateOrangesPharmaceutical PreparationsPhosphatidylinositol 4,5-DiphosphatePhosphatidylinositolsPhysiologicalPlayPotassium ChannelProcessProteinsPublishingRestRoleRotationSignal TransductionSiteStructureSurfaceTestingXenopus oocytealpha helixcofactordesigndrug developmentexperimental studyfluorophoreheart rhythmimprovednovelpreventsensorsimulationtraffickingvoltage
项目摘要
Project Summary
This project is to reveal the mechanism of how voltage, phosphatidylinositol 4,5-bisphosphate (PIP2) and
calmodulin (CaM) integrate to activate the IKs potassium ion channels in the heart. The IKs channel is important
for repolarization of cardiac action potentials and the control of heart rhythm. CaM and the membrane lipid PIP2
are important cell signals, and meanwhile these molecules are cofactors of the IKs channel required for channel
opening. These enable the IKs channel to play a critical role in the adaptation of heart rhythm to various
physiological conditions. Congenital and drug induced IKs malfunction is associated with cardiac arrhythmias.
Previous studies and our preliminary data indicate that the IKs channel is a novel target for antiarrhythmic therapy.
The significance of this study is to improve the understanding of molecular basis of cardiac electrophysiology
and antiarrhythmic drug development.
At present how CaM and PIP2 interact with the IKs channel is not clear. This proposal is motivated by the
recently published structural data of the channel protein. Combining these data with other published and our
preliminary studies lead to an exciting hypothesis for how CaM, PIP2 and voltage integrate to activate the IKs
channels. Our specific aims are designed to examine three key aspects of this hypothesis. We will use
electrophysiological approaches, fluorescence spectroscopy, structure-informed mutagenesis and molecular
dynamic simulations to study the IKs channels expressed in exogenous expression cells including Xenopus
oocytes and mammalian cell lines. These studies will reveal the binding of PIP2 and CaM to the channel protein
and subsequent conformational changes that open the channel. These results will provide a molecular basis to
understand how heart rhythm is regulated by cell signals and multiple mechanisms for drugs to target and modify,
which may lead to the development of more effective and safe antiarrhythmic drugs.
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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Jianmin Cui其他文献
Jianmin Cui的其他文献
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{{ truncateString('Jianmin Cui', 18)}}的其他基金
MANIPULATING IKS AS A THERAPEUTIC APPROACH TO CARDIAC ARRHYTHMIAS
操纵 IKS 作为心律失常的治疗方法
- 批准号:
8978576 - 财政年份:2015
- 资助金额:
$ 62.58万 - 项目类别:
MANIPULATING IKS AS A THERAPEUTIC APPROACH TO CARDIAC ARRHYTHMIAS
操纵 IKS 作为心律失常的治疗方法
- 批准号:
9098832 - 财政年份:2015
- 资助金额:
$ 62.58万 - 项目类别:
SUBUNITS INTERACTION IN THE FUNCTION OF BK CHANNELS
BK 通道功能中的亚基相互作用
- 批准号:
8410089 - 财政年份:2010
- 资助金额:
$ 62.58万 - 项目类别:
SUBUNITS INTERACTION IN THE FUNCTION OF BK CHANNELS
BK 通道功能中的亚基相互作用
- 批准号:
8212045 - 财政年份:2010
- 资助金额:
$ 62.58万 - 项目类别:
SUBUNITS INTERACTION IN THE FUNCTION OF BK CHANNELS
BK 通道功能中的亚基相互作用
- 批准号:
7782002 - 财政年份:2010
- 资助金额:
$ 62.58万 - 项目类别:
SUBUNITS INTERACTION IN THE FUNCTION OF BK CHANNELS
BK 通道功能中的亚基相互作用
- 批准号:
8020026 - 财政年份:2010
- 资助金额:
$ 62.58万 - 项目类别:
Ca2+ Dependent K+ Channels: Allosteric Gating
Ca2 依赖性 K 通道:变构门控
- 批准号:
7822275 - 财政年份:2009
- 资助金额:
$ 62.58万 - 项目类别: