Activation and Inhibition Mechanisms of Calcium-Activated Nonselective Cation Channels
钙激活非选择性阳离子通道的激活和抑制机制
基本信息
- 批准号:10503201
- 负责人:
- 金额:$ 66.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-01 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAmino Acid MotifsBindingBinding SitesBrugada syndromeCRISPR/Cas technologyCalciumCardiacCardiovascular systemCationsCellsClinicalClustered Regularly Interspaced Short Palindromic RepeatsCryoelectron MicroscopyDNA Sequence AlterationDataDiseaseExhibitsFluorometryHumanImmune systemInheritedInterventionIon ChannelKnock-in MouseKnowledgeLeadLinkMembraneMembrane PotentialsMethodsModelingMolecularMolecular ConformationMonitorMonovalent CationsMutationNervous system structureOrganPermeabilityPharmacologic SubstancePhenotypePhysiologicalPlayProcessPropertyRoleSideSignal TransductionSiteSkinStructureSyndromeTRPM5 geneTestingTissuesbasedisease phenotypefluorescence imaginggain of functiongain of function mutationhuman diseaseinhibitorinterdisciplinary approachmouse modelmutantnovelpatch clampskin disordervoltage
项目摘要
Project Summary
Ca2+-activated nonselective cation (CAN) channels are among a few ion channels that convert
intracellular Ca2+ signaling into changes in membrane potential, in contrast to most ion
channels that directly or indirectly use membrane potential to regulate intracellular Ca2+
signaling. This unique property allows CAN channels to play critical roles in many tissues and
organs. While the existence of CAN channels has been known for decades, recent evidence
has established that monovalent cation-permeable TRPM4 and TRPM5 are the long sought
for CAN channels. Indeed, numerous TRPM4 mutations are linked to severe human diseases,
e.g., cardiac conduction block, Bragada syndrome, PSEK (a skin disease). Despite their
functional significance, little is known about the molecular mechanisms governing TRPM4&5
channels activity. Ca2+ is the only known physiological activator for them, though membrane
potential also regulates channel activity but only in the presence of Ca2+. However, while the
Ca2+-binding sites have been identified by cryo-EM studies, how Ca2+ and voltage activate
TRPM4&5 channels remains unknown. Furthermore, while most known disease-causing
TRPM4 mutations lead to a gain-of-function phenotype, no effective inhibitor for TRPM4&5 is
currently available. Based on our preliminary functional data on TRPM4 Ca2+ and voltage
activation, our discovery of novel TRPM4 mutations causing human skin disease, a new
disease-causing mutant channel CRISPR mouse model exhibiting skin phenotypes, and our
recent discovery of a novel TRPM4 inhibition process, we plan to use a multidisciplinary
approach aiming at revealing the fundamental mechanisms of TRPM4&5 activation and
inhibition.
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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Juan Du其他文献
Akt regulates the fertility of Coridius chinensis by insulin signaling pathway
阿克泰通过胰岛素信号通路调控中华稻蝗的生殖力
- DOI:
10.1038/s41598-024-78416-0 - 发表时间:
2024-11-20 - 期刊:
- 影响因子:3.900
- 作者:
Jinyu Feng;Juan Du;Shangwei Li;Xingxing Chen - 通讯作者:
Xingxing Chen
Juan Du的其他文献
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{{ truncateString('Juan Du', 18)}}的其他基金
Structural Basis of Nociceptor Channel TRPM3 gating and pharmacology
伤害感受器通道 TRPM3 门控和药理学的结构基础
- 批准号:
10735377 - 财政年份:2023
- 资助金额:
$ 66.28万 - 项目类别:
Deep-learning methods based computational modeling
基于深度学习方法的计算建模
- 批准号:
10816248 - 财政年份:2022
- 资助金额:
$ 66.28万 - 项目类别:
Activation and Inhibition Mechanisms of Calcium-Activated Nonselective Cation Channels
钙激活非选择性阳离子通道的激活和抑制机制
- 批准号:
10629410 - 财政年份:2022
- 资助金额:
$ 66.28万 - 项目类别:
Structural and functional studies of the TRPM2 channel
TRPM2通道的结构和功能研究
- 批准号:
10604261 - 财政年份:2019
- 资助金额:
$ 66.28万 - 项目类别:
Structural and functional studies of the TRPM2 channel
TRPM2通道的结构和功能研究
- 批准号:
10413415 - 财政年份:2019
- 资助金额:
$ 66.28万 - 项目类别:
Structural and functional studies of the TRPM2 channel
TRPM2通道的结构和功能研究
- 批准号:
9896879 - 财政年份:2019
- 资助金额:
$ 66.28万 - 项目类别:
Structural and functional studies of the TRPM2 channel
TRPM2通道的结构和功能研究
- 批准号:
10386771 - 财政年份:2019
- 资助金额:
$ 66.28万 - 项目类别:
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Grant-in-Aid for General Scientific Research (C)














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