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

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

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ROBERT J BLOCH其他文献

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{{ 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:
A Novel Xenograft Model of FSHD
一种新型的 FSHD 异种移植模型
  • 批准号:
    8930205
  • 财政年份:
    2014
  • 资助金额:
    $ 55.55万
  • 项目类别:
A Novel Xenograft Model of FSHD
一种新型的 FSHD 异种移植模型
  • 批准号:
    8824131
  • 财政年份:
    2014
  • 资助金额:
    $ 55.55万
  • 项目类别:
Intermediate Filaments & Costamere Structure & Function
中间丝
  • 批准号:
    7942886
  • 财政年份:
    2009
  • 资助金额:
    $ 55.55万
  • 项目类别:
Obscurin & Myofibrils in Cardiac & Skeletal Muscle
暗色素
  • 批准号:
    7822220
  • 财政年份:
    2009
  • 资助金额:
    $ 55.55万
  • 项目类别:
Intermediate Filaments & Costamere Structure & Function
中间丝
  • 批准号:
    7590621
  • 财政年份:
    2009
  • 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:
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