Phosphorylation-dependent regulation of calcium channels by macromolecular complexes

大分子复合物对钙通道的磷酸化依赖性调节

基本信息

  • 批准号:
    9979954
  • 负责人:
  • 金额:
    $ 73.02万
  • 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:
    2019-08-01 至 2023-05-31
  • 项目状态:
    已结题

项目摘要

Our overall goal is to discover details of fundamental mechanisms underlying regulation of CaV1.2 channels that have eluded more than four decades of investigation. We propose to use novel tools and approaches to identify novel proteins, supramolecular complexes, and signaling pathways affecting CaV1.2 channels as the basis for targeted drug development for arrhythmias. Although it is well-established that phosphorylation by cyclic AMP (cAMP)-PKA, but not Ca2+/calmodulin kinase II (CaMKII), is the fundamental process by which b- adrenergic stimulation controls Ca2+ influx via CaV1.2 in the heart, the molecular targets of PKA remain unknown. A detailed molecular understanding of CaV1.2 regulation in myocytes has been hampered by the inability to recapitulate and then dissect in heterologous expression systems key aspects of CaV1.2 function in myocytes. Our novel tools surmount major obstacles that have limited progress in the field, and allow us to identify the neighboring proteome of CaV1.2 in the heart and probe molecular aspects of CaV1.2 regulation, using biochemical and electrophysiological techniques, within the context of cardiomyocytes, but with the power of a heterologous expression system. The failure thus far to identify any site as essential for adrenergic modulation led us to propose an alternative hypothesis: that a combination of phosphorylation sites in a1C is required for b-adrenergic stimulation of CaV1.2. To address this hypothesis, we generated mice with alanine- substitutions in rabbit a1C of all conserved and non-conserved consensus PKA phosphorylation sites (“35- mutant a1C”), and found that b-adrenergic regulation was not dependent upon any of these serine or threonine residues. Using a similar transgenic approach, we found that b-adrenergic regulation does not require phosphorylation of any of the 18 N-terminal, HOOK and GK domain consensus PKA phosphorylation sites in the b2b subunit. The next step is to create transgenic mice expressing b2b subunits with all PKA consensus sites removed (“33-mutant b2b”) and test regulation in a b2 knockout background. Thereafter, we will determine whether phosphorylation of either a1C or b subunits is sufficient to enable b-adrenergic regulation by crossing the 35-mutant a1C and the 33-mutant b2b mice. If adrenergic regulation is preserved, these results would shift a four-decade paradigm: the core CaV1.2 subunits are not the required PKA targets. Other aims of the proposal are to determine whether b-adrenergic stimulation of CaV1.2 is dependent upon a target extrinsic to CaV1.2 core subunits, and whether specifically attenuating b-adrenergic-modulation of CaV1.2 can suppress arrhythmogenesis. The feasibility of this approach is supported by the demonstration that disrupting the b-a interaction prevents b-adrenergic regulation of CaV1.2. The three Aims, which will provide key new understandings concerning the regulation of Ca2+ influx in cardiomyocytes, are highly relevant towards understanding cardiac pathologies and the molecular mechanisms responsible for the modulation of cardiac contractility.
我们的总体目标是发现CaV1.2通道调控的基本机制细节

项目成果

期刊论文数量(0)
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Steven O Marx其他文献

Steven O Marx的其他文献

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{{ truncateString('Steven O Marx', 18)}}的其他基金

Roles of Rad and other CaV1.2 neighboring proteins in regulating cardiac function in health and disease
Rad 和其他 CaV1.2 邻近蛋白在健康和疾病中调节心脏功能中的作用
  • 批准号:
    10628915
  • 财政年份:
    2023
  • 资助金额:
    $ 73.02万
  • 项目类别:
Investigating Cardiac Ion Channels by Novel Methods
通过新方法研究心脏离子通道
  • 批准号:
    10219521
  • 财政年份:
    2021
  • 资助金额:
    $ 73.02万
  • 项目类别:
Dynamic changes of the Nav1.5 interactome and contributions to heart failure
Nav1.5 相互作用组的动态变化及其对心力衰竭的影响
  • 批准号:
    10478131
  • 财政年份:
    2021
  • 资助金额:
    $ 73.02万
  • 项目类别:
Investigating Cardiac Ion Channels by Novel Methods
通过新方法研究心脏离子通道
  • 批准号:
    10418713
  • 财政年份:
    2021
  • 资助金额:
    $ 73.02万
  • 项目类别:
Dynamic changes of the Nav1.5 interactome and contributions to heart failure
Nav1.5 相互作用组的动态变化及其对心力衰竭的影响
  • 批准号:
    10317712
  • 财政年份:
    2021
  • 资助金额:
    $ 73.02万
  • 项目类别:
Investigating Cardiac Ion Channels by Novel Methods
通过新方法研究心脏离子通道
  • 批准号:
    10673191
  • 财政年份:
    2021
  • 资助金额:
    $ 73.02万
  • 项目类别:
Dynamic changes of the Nav1.5 interactome and contributions to heart failure
Nav1.5 相互作用组的动态变化及其对心力衰竭的影响
  • 批准号:
    10658902
  • 财政年份:
    2021
  • 资助金额:
    $ 73.02万
  • 项目类别:
Phosphorylation-dependent regulation of calcium channels by macromolecular complexes
大分子复合物对钙通道的磷酸化依赖性调节
  • 批准号:
    10161818
  • 财政年份:
    2019
  • 资助金额:
    $ 73.02万
  • 项目类别:
Phosphorylation-dependent regulation of calcium channels by macromolecular complexes
大分子复合物对钙通道的磷酸化依赖性调节
  • 批准号:
    10425277
  • 财政年份:
    2019
  • 资助金额:
    $ 73.02万
  • 项目类别:
Calmodulin regulation of Na+ channels in neurons and cardiomyocytes
钙调蛋白对神经元和心肌细胞Na通道的调节
  • 批准号:
    8965516
  • 财政年份:
    2014
  • 资助金额:
    $ 73.02万
  • 项目类别:

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