Cytoskeletal Regulation of SERCA in Muscle
SERCA 在肌肉中的细胞骨架调节
基本信息
- 批准号:10463614
- 负责人:
- 金额:$ 55.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-10 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:ANK1 geneATP phosphohydrolaseAdrenergic AgentsAffinityAlternative SplicingAnisotropyAnkyrinsBindingBiological AssayBiomechanicsCOS CellsCa(2+)-Transporting ATPaseCalciumCell membraneChimeric ProteinsComplementComplexCyclic AMPCyclic AMP-Dependent Protein KinasesCytoskeletal ProteinsCytoskeletonDissociationEnzymesFluorescenceFluorescence Resonance Energy TransferFrequenciesFunctional disorderHealthHeartHomeostasisIn SituIntegral Membrane ProteinKineticsLearningLinkMeasuresMechanical StressMembraneMetabolic Clearance RateMethodsModelingMolecular ConformationMuscleMuscle ContractionMuscle ProteinsMyopathyPathogenicityPathway interactionsPeriodicityPhosphorylationPhysiologicalPlayPositioning AttributeProtein SplicingProteinsPumpRegulationRelaxationRoleRyanodine Receptor Calcium Release ChannelSERCA1SarcolemmaSarcomeresSarcoplasmic ReticulumSignal TransductionSkeletal MuscleStressStriated MusclesTestingTimeTubular formationcombatconnectinexperimental studyinsightmembermillisecondmutantnovelobscurinoverexpressionphospholambanreuptakesarcolipinsensorskeletaltherapeutic targetuptake
项目摘要
Activity in striated muscle is driven by changes in myoplasmic Ca2+ [Ca2+]i that arise largely from Ca2+ efflux
from the sarcoplasmic reticulum (SR) via the ryanodine receptor to initiate contraction, and reuptake of Ca2+
into the SR via the sarco-endoplasmic Ca2+ -ATPase (SERCA) to initiate relaxation. SERCA modulates [Ca2+]i
and the overall SR Ca2+ load, which in turn regulates contractile strength. SERCA binds to phospholamban
(PLN) and sarcolipin (SLN), which reduce its affinity for Ca2+. Phosphorylation of PLN or SLN alters their
interaction with SERCA that (after a short lag) increases its activity over a period of many minutes. Although
they would make excellent physiological sense, mechanisms to regulate SERCA at high frequencies (e.g.,
contraction to contraction) have not been described. Here we consider the hypothesis that the cytoskeleton
regulates SERCA1 in skeletal muscle on a msec time scale. We have shown that obscurin (Obscn) and small
ankyrin 1 (sAnk1) interact with PLN and SLN to regulate SERCA in skeletal muscle and heart. Obscn is an
~800 kDa cytoskeletal member of the titin superfamily that surrounds sarcomeres at M-bands and Z-disks.
sAnk1 (Ank1.5) is a ~17 kDa integral membrane protein and alternatively spliced product of the ANK1 gene
that concentrates in the SR around M-bands and Z-disks. Remarkably, sAnk1 binds Obscn, PLN, SLN and
SERCA directly. We show: (i) the 3-way complex of sAnk1, SERCA and SLN partially ablates SLN’s inhibition
of Ca2+-ATPase activity; (ii) Obscn increases the activity of SERCA bound to sAnk1 and SLN; (iii) sAnk1 binds
PLN; and (iv) a myopathic Obscn mutant increases SERCA activity by avidly binding PLN. Here we test
the novel hypothesis that Obscn and sAnk1 are biomechanical sensors that “tune” SERCA activity to the
mechanical stress of contraction. We posit a direct link from sarcomeres, thru Obscn to sAnk1 complexed with
SERCA and either SLN or PLN in the SR, such that contraction increases SERCA’s ATPase activity. We
consider 2 possible models: Model 1: Contraction leads to the dissociation of sAnk1 and SLN or PLN from
SERCA to activate it; Model 2: Contraction induces a conformational change in the complex to activate
SERCA. We will test our hypothesis and models in 4 Specific Aims: (1) To determine if sAnk1, P/SLN and
SERCA form complexes to regulate Ca2+-ATPase; (2) To determine if Obscn increases Ca2+-ATPase activity
by dissociating sAnk1 and PLN or SLN from SERCA, or by inducing a conformational change in the
complex; (3) To learn if the strength of contraction and the rates of Ca2+ clearance from the myoplasm are
governed by Obscn’s interactions with sAnk1 and PLN or SLN; and (4) To assess the effect of phosphorylation
on sAnk1’s role in regulating SERCA activity. These experiments have the potential to reveal novel
mechanisms regulating Ca2+ homeostasis in striated muscle, to offer fresh insights into the role that SERCA
plays in maintaining muscle health, and to suggest novel ways to manipulate SERCA’s activity to combat
myopathy.
横纹肌的活动是由肌浆Ca2+ [Ca2+]i的变化驱动的,这主要是由Ca2+外排引起的
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ROBERT J BLOCH其他文献
ROBERT J BLOCH的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ROBERT J BLOCH', 18)}}的其他基金
Cytoskeletal Regulation of SERCA in Muscle
SERCA 在肌肉中的细胞骨架调节
- 批准号:
10684668 - 财政年份:2020
- 资助金额:
$ 55.55万 - 项目类别:
Organization of Sarcoplasmic Reticulum in Skeletal Muscle
骨骼肌肌浆网的组织
- 批准号:
8265638 - 财政年份:2008
- 资助金额:
$ 55.55万 - 项目类别:
Organization of Sarcoplasmic Reticulum in Skeletal Muscle
骨骼肌肌浆网的组织
- 批准号:
7646300 - 财政年份:2008
- 资助金额:
$ 55.55万 - 项目类别:
Organization of Sarcoplasmic Reticulum in Skeletal Muscle
骨骼肌肌浆网的组织
- 批准号:
8077961 - 财政年份:2008
- 资助金额:
$ 55.55万 - 项目类别:
Organization of Sarcoplasmic Reticulum in Skeletal Muscle
骨骼肌肌浆网的组织
- 批准号:
7507262 - 财政年份:2008
- 资助金额:
$ 55.55万 - 项目类别: