Calmodulin regulation of Na+ channels in neurons and cardiomyocytes
钙调蛋白对神经元和心肌细胞Na通道的调节
基本信息
- 批准号:8965516
- 负责人:
- 金额:$ 51.43万
- 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:2014-11-15 至 2016-07-31
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAddressAffectAffinityArrhythmiaAtaxiaAutistic DisorderBindingBiochemicalC-terminalCalmodulinCardiacCardiac MyocytesCardiomyopathiesCellsConflict (Psychology)DataDiseaseEpilepsyFeedbackFunctional disorderGap JunctionsGenesGrantHealthInheritedIntellectual functioning disabilityKnowledgeLeadLigand Binding DomainLinkMediator of activation proteinMembraneMethodsModelingMutateMutationNeuronsPathologicPhysiologicalPhysiologyProcessRegulationResolutionRoleSCN1A proteinSCN2A proteinSchizophreniaSignal TransductionSiteStructureSudden infant death syndromeSyndromeSystemTestingTimecell typedisease-causing mutationinnovationmutantnovelnovel strategiessensorvoltage
项目摘要
DESCRIPTION (provided by applicant): Voltage-gated Na+ channelopathies are associated with multiple disorders. Mutations in neuronal Na+ channels cause epilepsy syndromes, ataxia, and autism; mutations in the cardiac Na+ channels are associated with arrhythmias, sudden infant death syndrome, conduction disorders, and cardiomyopathies. A hotspot for disease-causing mutations is the channels' C-terminal domain (CTD), which harbors a calmodulin (CaM) interaction site. Because Ca2+ is the ultimate signal of electrical activity and is often perturbed
in disease states, the presence of a key Ca2+ sensor (CaM) at a hotspot for channel regulation (the CTD) provides a starting point for understanding how these channelopathies cause disease. Nevertheless, regulation of Na+ channels by Ca2+/CaM is poorly understood and information is limited by the lack of structural information and challenges to investigating channel function in native cell types. Here, we build on new structural information and novel methods to investigate how Ca2+/CaM regulates Na+ channels in the context of native cell types. Our new structural information provides background and guideposts for investigating how Ca2+-free (apo) CaM and Ca2+-loaded CaM differently affect channel function; how neuronal and cardiac channels are distinctly regulated by CaM in their native cell types, and how different CaM interacting domains within Na+ channels contribute to overall Ca2+/CaM-dependent regulation. Our novel methods of studying informative mutants in cardiomyocytes and neurons will provide an understanding of how Ca2+ affects Na+ channels and thus how Ca2+ dysregulation leads to the various Na+ channelopathies. The specific Aims addressed in this proposal are to determine: 1) How Ca2+-free apoCaM controls NaV function in neurons and cardiomyocytes; 2) How Ca2+/CaM interaction with the NaV CTD controls NaV function in neurons and cardiomyocytes; and 3) How Ca2+/CaM interaction with the NaV III-IV intracellular linker controls NaV function in neurons and cardiomyocytes.
描述(由申请人提供):电压门控Na+通道病与多种疾病相关。神经元 Na+ 通道突变会导致癫痫综合征、共济失调和自闭症;心脏 Na+ 通道的突变与心律失常、婴儿猝死综合征、传导障碍和心肌病有关。导致疾病的突变的热点是通道的 C 末端结构域 (CTD),其中包含钙调蛋白 (CaM) 相互作用位点。因为 Ca2+ 是电活动的最终信号并且经常受到干扰
在疾病状态下,通道调节热点 (CTD) 上关键 Ca2+ 传感器 (CaM) 的存在为了解这些通道病如何导致疾病提供了起点。然而,人们对 Ca2+/CaM 对 Na+ 通道的调节知之甚少,并且由于缺乏结构信息以及研究天然细胞类型中通道功能的挑战,信息也受到限制。在这里,我们基于新的结构信息和新方法来研究 Ca2+/CaM 如何在天然细胞类型的背景下调节 Na+ 通道。我们的新结构信息为研究无 Ca2+ (apo) CaM 和负载 Ca2+ CaM 如何不同地影响通道功能提供了背景和指导;神经元和心脏通道如何在其天然细胞类型中受到 CaM 的明显调节,以及 Na+ 通道内不同的 CaM 相互作用域如何有助于整体 Ca2+/CaM 依赖性调节。我们研究心肌细胞和神经元中信息突变体的新方法将有助于了解 Ca2+ 如何影响 Na+ 通道,以及 Ca2+ 失调如何导致各种 Na+ 通道病。该提案的具体目标是确定: 1) 无 Ca2+ apoCaM 如何控制神经元和心肌细胞中的 NaV 功能; 2)Ca2+/CaM与NaV CTD的相互作用如何控制神经元和心肌细胞中的NaV功能; 3) Ca2+/CaM 与 NaV III-IV 细胞内连接子的相互作用如何控制神经元和心肌细胞中的 NaV 功能。
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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Steven O Marx其他文献
Steven O Marx的其他文献
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{{ truncateString('Steven O Marx', 18)}}的其他基金
Roles of Rad and other CaV1.2 neighboring proteins in regulating cardiac function in health and disease
Rad 和其他 CaV1.2 邻近蛋白在健康和疾病中调节心脏功能中的作用
- 批准号:
10628915 - 财政年份:2023
- 资助金额:
$ 51.43万 - 项目类别:
Dynamic changes of the Nav1.5 interactome and contributions to heart failure
Nav1.5 相互作用组的动态变化及其对心力衰竭的影响
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10478131 - 财政年份:2021
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$ 51.43万 - 项目类别:
Investigating Cardiac Ion Channels by Novel Methods
通过新方法研究心脏离子通道
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10219521 - 财政年份:2021
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$ 51.43万 - 项目类别:
Investigating Cardiac Ion Channels by Novel Methods
通过新方法研究心脏离子通道
- 批准号:
10418713 - 财政年份:2021
- 资助金额:
$ 51.43万 - 项目类别:
Dynamic changes of the Nav1.5 interactome and contributions to heart failure
Nav1.5 相互作用组的动态变化及其对心力衰竭的影响
- 批准号:
10317712 - 财政年份:2021
- 资助金额:
$ 51.43万 - 项目类别:
Investigating Cardiac Ion Channels by Novel Methods
通过新方法研究心脏离子通道
- 批准号:
10673191 - 财政年份:2021
- 资助金额:
$ 51.43万 - 项目类别:
Dynamic changes of the Nav1.5 interactome and contributions to heart failure
Nav1.5 相互作用组的动态变化及其对心力衰竭的影响
- 批准号:
10658902 - 财政年份:2021
- 资助金额:
$ 51.43万 - 项目类别:
Phosphorylation-dependent regulation of calcium channels by macromolecular complexes
大分子复合物对钙通道的磷酸化依赖性调节
- 批准号:
10161818 - 财政年份:2019
- 资助金额:
$ 51.43万 - 项目类别:
Phosphorylation-dependent regulation of calcium channels by macromolecular complexes
大分子复合物对钙通道的磷酸化依赖性调节
- 批准号:
10425277 - 财政年份:2019
- 资助金额:
$ 51.43万 - 项目类别:
Phosphorylation-dependent regulation of calcium channels by macromolecular complexes
大分子复合物对钙通道的磷酸化依赖性调节
- 批准号:
9979954 - 财政年份:2019
- 资助金额:
$ 51.43万 - 项目类别:
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