Role of a-actinin in Cav1.2 Function

a-肌动蛋白在 Cav1.2 功能中的作用

基本信息

  • 批准号:
    9924426
  • 负责人:
  • 金额:
    $ 50.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-08-15 至 2022-04-30
  • 项目状态:
    已结题

项目摘要

Role of α-actinin in Cav1.2 Function Abstract L-type Ca2+ channels are tightly coupled to gene transcription, control neuronal excitability, and mediate multiple forms of synaptic plasticity. Yet its cell biology and regulation is remarkably poorly understood. Our long term interest is to determine the molecular mechanisms that regulate the L-type channel Cav1.2 (e.g., Science 293, 98; Science 293, 2205; PNAS 103, 7500; Neuron 78, 483), which is the most prevalent L-type channel in brain and heart. We recently found that α-actinin binds directly to the IQ motif of the central pore- forming Cav1.2 subunit α11.2 and augments its surface localization (Neuron 78, 483). We now identify three point mutations in the IQ motif that individually impair α-actinin binding. Our preliminary electrophysiological and surface labeling data suggest that impairing α-actinin binding to the IQ motif decreases surface expression and, unexpectedly, also channel open probability (Po). Aim 1 is the very first comprehensive analysis of trafficking kinetics of WT and point mutated Cav1.2 through the ER-Golgi-TGN secretory pathway and endocytic recycling and degradation pathway by surface biotinylation, N-glycosylation analysis and colocalization with respective markers like BiP and Rab5. Aim 2 is to determine and compare current density, gating currents, and single channel currents to test whether the α-actinin binding - deficient point mutations of Cav1.2 have decreased Po. Our structural analysis is guiding charge reversal experiments for unequivocal (!) assignment of deficits in surface expression and Po in the Cav1.2 mutants to loss of α-actinin binding. We found that Ca2+ influx specifically through Cav1.2 leads to displacement of α-actinin from the IQ motif by Ca2+/calmodulin and in parallel to run down of Cav1.2 via endocytosis and reduction in Po. Aim 3 is to unravel the interplay between α-actinin and calmodulin at the IQ motif to precisely define the molecular mechanisms of how Ca2+/calmodulin displaces α-actinin and leads to endocytosis and run down of Cav1.2. Aim 4 will test first the role of α-actinin in neuronal Cav1.2 functions including Ca2+ influx into spines and regulation of gene expression via NFAT and then why α-actinin association and, fittingly, surface expression of Cav1.2 is increased in rodent models of senility and Alzheimer’s disease (AD). Increased Cav1.2 channel activity contributes to senile symptoms and AD (e.g., Science 272, 1017; Science 243, 809). Cav1.2 also plays an important role in PTSD and dysregulation of Cav1.2 leads to autism spectrum disorders (Cell 119, 19-31). Thus our work on the functional interplay of Cav1.2 with α-actinin and calmodulin is of high significance for understanding and ultimately treatment of these brain diseases. On a broader perspective it is of physiological importance as it will define important aspects that govern the functional availability of Cav1.2 with its manifold functions in neurons and beyond including learning and memory.
α- actitin在Cav1.2功能中的作用

项目成果

期刊论文数量(0)
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JOHANNES W HELL其他文献

JOHANNES W HELL的其他文献

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{{ truncateString('JOHANNES W HELL', 18)}}的其他基金

Postsynaptic Signaling by Norepinephrine and cAMP
去甲肾上腺素和 cAMP 的突触后信号传导
  • 批准号:
    10445917
  • 财政年份:
    2022
  • 资助金额:
    $ 50.16万
  • 项目类别:
Postsynaptic Signaling by Norepinephrine and cAMP
去甲肾上腺素和 cAMP 的突触后信号传导
  • 批准号:
    10557151
  • 财政年份:
    2022
  • 资助金额:
    $ 50.16万
  • 项目类别:
Detection of Synaptic Proteins with Fluorescent Molecular Rotor-labeled Peptides
使用荧光分子转子标记肽检测突触蛋白
  • 批准号:
    10063961
  • 财政年份:
    2019
  • 资助金额:
    $ 50.16万
  • 项目类别:
Dysregulation of Cav1.2 by beta amyloid peptide
β 淀粉样肽导致 Cav1.2 失调
  • 批准号:
    10521735
  • 财政年份:
    2016
  • 资助金额:
    $ 50.16万
  • 项目类别:
Role of a-actinin in Cav1.2 Function
a-肌动蛋白在 Cav1.2 功能中的作用
  • 批准号:
    9333166
  • 财政年份:
    2016
  • 资助金额:
    $ 50.16万
  • 项目类别:
Molecular Mechanisms of Postsynaptic AMPA Receptor Localization
突触后 AMPA 受体定位的分子机制
  • 批准号:
    8935917
  • 财政年份:
    2014
  • 资助金额:
    $ 50.16万
  • 项目类别:
Molecular Mechanisms of Postsynaptic AMPA Receptor Localization
突触后 AMPA 受体定位的分子机制
  • 批准号:
    9093834
  • 财政年份:
    2014
  • 资助金额:
    $ 50.16万
  • 项目类别:
Molecular Mechanisms of Postsynaptic AMPA Receptor Localization
突触后 AMPA 受体定位的分子机制
  • 批准号:
    8818208
  • 财政年份:
    2014
  • 资助金额:
    $ 50.16万
  • 项目类别:
Signaling by cAMP within Postsynaptic Nanodomains
突触后纳米结构域内的 cAMP 信号传导
  • 批准号:
    8439852
  • 财政年份:
    2012
  • 资助金额:
    $ 50.16万
  • 项目类别:
Signaling by cAMP within postsynaptic nano domains R01NS078792
突触后纳米域内 cAMP 的信号传导 R01NS078792
  • 批准号:
    9066462
  • 财政年份:
    2012
  • 资助金额:
    $ 50.16万
  • 项目类别:

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