The Molecular Transitions that Initiate EC Coupling in Skeletal Muscle
The Molecular Transitions that Initiate EC Coupling in Skeletal Muscle
批准号:
10594420
负责人:
Riccardo Olcese
金额:
$39.0万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
未结题
起止时间:
2019-06-01 至 2025-03-31
关键词:
Adaptor Signaling ProteinAddressAdultAffectComplexComputational TechniqueCouplingDependenceElectrophysiology (science)ElementsEmbryoFluorometryInvestigationIon ChannelIonsKnowledgeL-Type Calcium ChannelsLaboratoriesMacromolecular ComplexesMalignant hyperpyrexia due to anesthesiaMediatingMolecularMolecular ConformationMotivationMovementMuscleMuscle ContractionMutationOocytesOpticsPhysiologyPositioning AttributeProteinsRNA SplicingRegulationResearch PersonnelRyanodine Receptor Calcium Release ChannelSarcoplasmic ReticulumSignal TransductionSkeletal MuscleSystemVariantbiophysical propertiesmuscle physiologyoperationsensorskeletalvoltagevoltage clamp
中文摘要
项目摘要/摘要
这些研究的动机是需要了解基本的生物物理学
骨骼肌电压门控L型钙通道CaV1.1的特性而离子传导是一种
绝大多数离子通道的关键特征(通常也是唯一的职责),CaV1.1在某种程度上
独一无二的:它的电压传感器的激活打开了它的毛孔,但不需要钙离子进入来触发
肌肉收缩。相反,Cav1.1电压传感器的构象变化直接门控
兰尼定受体(RyR1)通过这两个通道之间的物理耦合来触发释放
肌浆网钙离子。在此背景下,Cav1.1的四个电压传感元件确实是
RyR1通道的电压传感器。由于在卵母细胞中表达Cav1.1通道的可能性
最近由于发现了一种重要的适配器蛋白(Stac3),Olcese变得可行
实验室处于有利地位,可以直接研究电压调节的机制
蛋白质,具有实现尖端电压钳荧光测量的独特能力(到目前为止)
进近CAV航道。
在接下来的五年里,利用电生理、光学和计算技术,
研究人员将描绘CaV1.1通道中电压依赖的基础,在成人和
胚胎剪接变体。他们将询问这种电压依赖是如何由
辅助亚基(β,α2δ和γ)参与CaV1.1大分子复合体的形成。他们会
确定四个同源但不相同的CaV1.1电压感应域中的哪个授予
电压对RyR1介导的钙释放的敏感性。最后,调查人员将解决分子
一种引起恶性高热的突变对电压敏感产生特异性影响的机制
CAV1.1的仪器。所收集的知识对于理解
肌肉生理学和对收缩的电压依赖控制。
英文摘要
PROJECT SUMMARY/ABSTRACT
The motivation for these studies is the need to gain an understanding of the fundamental biophysical
properties of the skeletal voltage-gated L-type Calcium channel CaV1.1. While ion conduction is a
critical feature (and often the only duty) of the vast majority of ion channels, CaV1.1 is somewhat
unique: the activation of its voltage sensors opens its pore, but Ca2+ entry is not required to trigger
muscle contraction. Instead, the conformational changes of Cav1.1 voltage sensors directly gate
Ryanodine receptors (RyR1) via a physical coupling between these two channels, to trigger the release
of sarcoplasmic reticulum Ca2+. In this context, the four voltage-sensing elements of Cav1.1 are indeed
the voltage sensors of RyR1 channels. As the possibility to express Cav1.1 channel in oocytes has
recently become feasible thanks to the discovery of an essential adaptor protein (Stac3), the Olcese
laboratory is in a privileged position to directly address the mechanism of voltage regulation in this
protein, with a unique capability (to date) to implement the cutting-edge voltage clamp fluorometry
approach to CaV channels.
During the next five years, using electrophysiological, optical and computational techniques, the
investigators will delineate the basis of voltage dependence in CaV1.1 channels, in both adult and
embryonic splice variants. They will interrogate how this voltage dependence is modulated by the
participation of auxiliary subunits (β, α2δ, and γ) in the CaV1.1 macromolecular complex. They will
determine which of the four homologous, but non-identical CaV1.1 Voltage Sensing Domains confer
voltage sensitivity to RyR1-mediated Ca release. Finally, the investigators will address the molecular
mechanism of a malignant-hyperthermia-causing mutation that specifically affects the voltage-sensing
apparatus of CaV1.1. The knowledge gathered by is critical to understand fundamental aspects of
muscle physiology and the voltage-dependent control of contraction.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
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资助金额:$54.61万
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依托单位:
The Molecular Transitions that Initiate EC Coupling in Skeletal Muscle
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批准号:10371036
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Voltage-driven Structural Transitions in Voltage-Gated Calcium Channels
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Voltage-driven Structural Transitions in Voltage-Gated Calcium Channels
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批准号:9389512
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Voltage-driven Structural Transitions in Voltage-Gated Calcium Channels
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BK(Ca) channel in heart mitochondria
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Molecular Approaches to Arrhythmia Therapy
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批准号:8852673
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财政年份:2005
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依托单位:
Molecular Approaches to Arrhythmia Therapy
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批准号:8376291
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项目类别:
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资助金额:$29.4万
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财政年份:2005
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依托单位:
Molecular Approaches to Arrhythmia Therapy
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批准号:8680308
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项目类别:
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资助金额:$28.81万
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财政年份:2005
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依托单位:
Molecular Approaches to Arrhythmia Therapy
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批准号:8479415
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项目类别:
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依托单位:
Molecular Approaches to Arrhythmia Therapy
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批准号:8133292
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项目类别:
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资助金额:$29.66万
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负责人:Riccardo Olcese
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依托单位:
Structural Changes in BKCa Channels During Gating
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批准号:7614403
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项目类别:
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资助金额:$36.19万
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财政年份:2002
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Structural Changes in BKCa Channels During Gating
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财政年份:2002
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Structural Changes in BKCa Channels During Gating
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资助金额:$36.19万
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Structural Changes in BKCa Channels During Gating
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Structural Changes in BKCa Channels During Gating
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海外基金