14-3-3 regulation of cardiac L-type calcium channels and EC-coupling
14-3-3 心脏 L 型钙通道和 EC 偶联的调节
基本信息
- 批准号:10536570
- 负责人:
- 金额:$ 3.91万
- 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:2022-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectApoptosisBasic ScienceBehaviorBindingBinding SitesBiotinylationC-terminalCardiacCardiac MyocytesCardiomyopathiesCellsComplexConsensusCouplingCyclic AMP-Dependent Protein KinasesDataDependenceDevelopmentElectrophysiology (science)ForskolinGoalsHeartHeart DiseasesInvestigationIon ChannelIonsIsoproterenolKnowledgeL-Type Calcium ChannelsLinkMeasuresMediatingMicroscopyMissionModalityModelingMolecularMuscle CellsNational Heart, Lung, and Blood InstitutePhosphoric Monoester HydrolasesPhosphorylationPhosphorylation SitePhosphoserinePhysiological ProcessesPlayProbabilityPropertyProtein IsoformsProteinsReceptor SignalingRegulationRegulatory PathwayReportingResolutionRoleSarcolemmaSignal PathwaySiteSodium ChannelSurfaceTailTestingThreonineVentricularadenoviral-mediatedbeta-adrenergic receptorcell growthdensityfightinghemodynamicsinsightnanoscalenew therapeutic targetoverexpressionpre-doctoralprotein functionresponsetraffickingvoltage
项目摘要
Project Summary: The voltage-gated L-type calcium channel (CaV1.2) is essential for cardiac excitation-
contraction (EC)-coupling and dysregulation of the channel is implicated in many forms of heart disease. 14-3-3
is a ubiquitous protein that interacts with numerous cellular proteins to affect multiple physiological processes
including cell growth, apoptosis, and ion channel trafficking. It preferentially binds phospho-serine/threonine
residues on target proteins to regulate their trafficking, cooperativity, phosphorylation state, and/or activity. In
HEK293 cells, 14-3-3 enhances trafficking of another voltage gated Ca2+ channel (CaV2.2) and has been shown
to indirectly alter CaV1.2 trafficking via interactions with CaVβ subunits, however direct evidence and information
about the extent and phosphorylation-dependence of this regulation is still needed. In addition, there have been
no investigations into the role of 14-3-3 in CaV1.2 channel trafficking/regulation in cardiomyocytes. We address
these gaps in knowledge in the current application. Since 14-3-3 has been reported to facilitate cooperative
gating of the voltage-dependent cardiac Na+ channel, NaV1.5, we will also investigate the role of 14-3-3 in
cooperative interactions of CaV1.2. This gating modality of CaV1.2 occurs when allosteric interactions form
between C-terminal tails of adjacent channels in a cluster such that the opening of one channel can be
communicated to other attached channels to enhance their open probability and amplify whole-cell Ca2+ influx.
Our group has previously shown that PKA-mediated phosphorylation of CaV1.2 channels triggers enhanced
trafficking of these channels into the sarcolemma of ventricular myocytes, producing larger channel clusters that
facilitate enhanced cooperative gating behavior and augmented whole-cell Ca2+ currents. This helps tune cardiac
EC-coupling to meet the enhanced demand during fight-or-flight. However, the molecular details of this enhanced
trafficking are unclear. Here we propose that 14-3-3 plays a role in this response. We have identified several
putative binding sites for 14-3-3 on the C-tail of CaV1.2 and other critical regulatory sites, including consensus
PKA phosphorylation sites. This project aims to test the hypothesis that 14-3-3 regulates CaV1.2 trafficking,
resulting in enhanced channel clustering on the sarcolemma that facilitates cooperative interactions and
amplifies Ca2+ influx. We further propose that these interactions are strengthened by channel
phosphorylation providing a means to tune CaV1.2 channel activity and EC-coupling to meet demand. In
this two-year predoctoral project, we will rigorously test this hypothesis in three Specific Aims. Aim 1 tests the
hypothesis that 14-3-3 interacts with CaV1.2 in a phosphorylation-dependent manner. Aim 2 tests the hypothesis
that CaV1.2 channel trafficking, sarcolemmal clustering, and cooperative interactions are enhanced by 14-3-3.
Aim 3 focuses on the functional effects of this regulation on cardiac EC-coupling. Alterations in CaV1.2 channel
trafficking and regulation are associated with numerous cardiomyopathies given its central role in cardiac EC-
coupling; thus our goals are relevant to the mission of the NHLBI.
项目概述:电压门控L型钙通道(CaV1.2)对心脏兴奋至关重要-
该通道的收缩(EC)偶联和失调与许多形式的心脏病有关。14-3-3
是一种普遍存在的蛋白质,与许多细胞蛋白质相互作用,影响多种生理过程
包括细胞生长、凋亡和离子通道运输。优先结合磷酸丝氨酸/苏氨酸
靶蛋白上的残基以调节它们的运输、协同性、磷酸化状态和/或活性。在
HEK 293细胞,14-3-3增强另一种电压门控Ca 2+通道(CaV2.2)的运输,并已显示
通过与CaVβ亚基的相互作用间接改变CaV 1.2的运输,然而,直接证据和信息
关于这种调节的程度和磷酸化依赖性仍然是需要的。此外,
没有研究14-3-3在心肌细胞中CaV1.2通道运输/调节中的作用。我们解决
这些知识的差距在当前的应用。自14-3-3以来,已报告,以促进合作
门控的电压依赖性心脏Na+通道,NaV1.5,我们还将研究14-3-3在
CaV1.2的协同作用。当变构相互作用形成时,CaV1.2的这种门控模式发生
在簇中的相邻通道的C-末端尾部之间,使得一个通道的开口可以
与其他附着通道连通,以提高其开放概率并放大全细胞Ca 2+内流。
我们的小组先前已经表明,PKA介导的CaV1.2通道磷酸化触发增强的CaV1.2通道磷酸化。
将这些通道运输到心室肌细胞的肌膜中,产生更大的通道簇,
促进增强的协同门控行为和增强的全细胞Ca 2+电流。这有助于调整心脏
EC耦合,以满足战斗或飞行期间的增强需求。然而,这种增强的分子细节
贩运不明确。在这里,我们提出14-3-3在这种反应中起作用。我们发现了几个
CaV1.2的C-尾上14-3-3的推定结合位点和其他关键调控位点,包括共有位点
PKA磷酸化位点。该项目旨在测试14-3-3调节CaV1.2运输的假设,
导致肌膜上的增强的通道聚集,这促进了协作性相互作用,
增加Ca 2+内流。我们进一步提出,这些相互作用是由通道加强
磷酸化提供了调节CaV1.2通道活性和EC偶联以满足需求的手段。在
在这个为期两年的博士前项目中,我们将在三个具体目标中严格检验这一假设。目标1测试
假设14-3-3以磷酸化依赖性方式与CaV1.2相互作用。目标2检验假设
CaV1.2通道运输、肌膜聚集和合作相互作用被14-3-3增强。
目的3关注这种调节对心脏EC偶联的功能影响。CaV1.2通道改变
运输和调节与许多心肌病有关,因为它在心脏EC中起着核心作用,
因此,我们的目标与NHLBI的使命相关。
项目成果
期刊论文数量(0)
专著数量(0)
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专利数量(0)
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Heather Spooner其他文献
Heather Spooner的其他文献
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{{ truncateString('Heather Spooner', 18)}}的其他基金
14-3-3 regulation of cardiac L-type calcium channels and EC-coupling
14-3-3 心脏 L 型钙通道和 EC 偶联的调节
- 批准号:
10753500 - 财政年份:2022
- 资助金额:
$ 3.91万 - 项目类别:
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