The Molecular Transitions that Initiate EC Coupling in Skeletal Muscle
骨骼肌中启动 EC 偶联的分子转变
基本信息
- 批准号:10371036
- 负责人:
- 金额:$ 39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-06-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 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 ChannelRyanodine ReceptorsSarcoplasmic ReticulumSignal TransductionSkeletal MuscleSystemVariantbiophysical propertiesmuscle physiologyoperationsensorskeletalvoltagevoltage clamp
项目摘要
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.
项目总结/摘要
这些研究的动机是需要了解基本的生物物理学
骨骼电压门控L型钙通道CaV1.1的特性。虽然离子传导是一种
CaV1.1是绝大多数离子通道的关键特征(通常也是唯一的职责),
独特:其电压传感器的激活打开其孔,但不需要Ca 2+进入触发
肌肉收缩。相反,Cav1.1电压传感器的构象变化直接门控
Ryanodine受体(RyR 1)通过这两个通道之间的物理耦合,触发释放
肌浆网Ca ~(2+)。在这种情况下,Cav1.1的四个电压传感元件确实是
RyR 1通道的电压传感器。由于Cav1.1通道在卵母细胞中表达的可能性,
由于发现了一种必需的衔接蛋白(Stac 3),Olcese
实验室处于一个特权地位,直接解决电压调节机制,在这一点上,
蛋白质,具有独特的能力(迄今为止),以实现尖端的电压钳荧光测定法
接近CaV通道。
在接下来的五年里,利用电生理学、光学和计算技术,
研究者将描述CaV1.1通道电压依赖性的基础,
胚胎剪接变体。他们将询问这种电压依赖性是如何被调制的。
辅助亚基(β、α2δ和γ)参与CaV1.1大分子复合物。他们将
确定四个同源但不相同的CaV1.1电压感应结构域中的哪一个赋予
电压敏感性RyR 1介导的钙释放。最后,研究人员将解决分子
一种引起恶性高热的突变机制,特异性地影响电压敏感
CaV1.1的装置。所收集的知识对于理解
肌肉生理学和收缩的电压依赖性控制。
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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Riccardo Olcese其他文献
Riccardo Olcese的其他文献
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{{ truncateString('Riccardo Olcese', 18)}}的其他基金
Sodium Dependent Inactivation of the Na+-Ca2+ exchange: Relevance to Cardiac Function
Na-Ca2 交换的钠依赖性失活:与心脏功能的相关性
- 批准号:
10531590 - 财政年份:2020
- 资助金额:
$ 39万 - 项目类别:
The Molecular Transitions that Initiate EC Coupling in Skeletal Muscle
骨骼肌中启动 EC 偶联的分子转变
- 批准号:
10594420 - 财政年份:2019
- 资助金额:
$ 39万 - 项目类别:
DRVCF, a new optical method for real-time, high resolution, intramolecular distance measurements in conducting ion channels
DRVCF,一种新的光学方法,用于传导离子通道中的实时、高分辨率、分子内距离测量
- 批准号:
9322172 - 财政年份:2017
- 资助金额:
$ 39万 - 项目类别:
The Late L-type Ca Current as the Target for a New Class of Antiarrhythmics
晚期 L 型 Ca 电流作为新型抗心律失常药物的靶点
- 批准号:
9915944 - 财政年份:2017
- 资助金额:
$ 39万 - 项目类别:
Voltage-driven Structural Transitions in Voltage-Gated Calcium Channels
电压门控钙通道中电压驱动的结构转变
- 批准号:
9178075 - 财政年份:2014
- 资助金额:
$ 39万 - 项目类别:
Voltage-driven Structural Transitions in Voltage-Gated Calcium Channels
电压门控钙通道中电压驱动的结构转变
- 批准号:
9389512 - 财政年份:2014
- 资助金额:
$ 39万 - 项目类别:
Voltage-driven Structural Transitions in Voltage-Gated Calcium Channels
电压门控钙通道中电压驱动的结构转变
- 批准号:
9277214 - 财政年份:2014
- 资助金额:
$ 39万 - 项目类别:
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