Postsynaptic Signaling by Norepinephrine and cAMP

去甲肾上腺素和 cAMP 的突触后信号传导

基本信息

  • 批准号:
    10445917
  • 负责人:
  • 金额:
    $ 47.14万
  • 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:
    2022-02-01 至 2026-12-31
  • 项目状态:
    未结题

项目摘要

Postsynaptic Signaling by Norepinephrine and cAMP Abstract Norepinephrine (NE) regulates attention and alertness. The β2AR adrenergic receptor (β2AR) is the prevalent postsynaptic NE effector at glutamatergic synapses, where it interacts with AMPARs and the postsynaptic L- type Ca2+ channel (LTCC) CaV1.2. These complexes also contain all downstream effectors of β2AR (Gs, adenylyl cyclases (ACs) and the cAMP-dependent protein kinase PKA) for highly localized signaling by cAMP (see our pioneering work in Science 293, 98; Science 293, 2205; EMBO J 29, 482; EMBO J 35, 1330; Science Signaling10, eaaf9659 and eaaf9647). Our exciting preliminary data indicate that 1) NE enters neurons and endosomes via the NE transporters OCT3 and PMAT to stimulate intracellular β2AR signaling and drive AMPARs to the cell surface; 2) the cAMP degrading phosphodiesterase PDE4A5, which is increased during sleep deprivation and mediates the resulting memory impairment, is linked to the β2AR - AMPAR complex via PSD- 95; 3) CaV1.2 forms a supercomplex with AMPARs, which allows efficient activation of CaV1.2 during synaptic transmission at postsynaptic sites with NE present. Aim 1 is to test whether activation of intracellular β2ARs upon NE uptake by OCT3 & PMAT triggers AMPAR phosphorylation and surface delivery, thereby promoting LTP as PKA is known to stimulate AMPAR surface insertion. We will test whether NE-induced phosphorylation (immunoblotting; IB) and surface insertion of GluA1 (immunofluorescent microscopy; IF) and NE-dependent LTP are abrogated by inhibitors and KO of OCT3 &PMAT. This will provide for the first time lacking but important evidence for intracellular signaling by NE in neurons. Aim 2 is to test whether the cAMP-hydrolyzing PDE4A5 curbs upregulation of AMPARs by β2AR - cAMP - PKA signaling. We will test whether displacing PDE4A5 from GluA1 with polypeptides elevates GluA1 phosphorylation by PKA and surface expression of GluA1 in HCs (IF) and postsynaptic AMPARs responses (mEPSC, EPSC). Aim 3 is to determine the AMPAR - CaV1.2 interaction sites and test the functional relevance of the AMPAR - CaV1.2 supercomplex formation. We will disrupt the interaction by mutations and acute peptide application to determine its role in Ca2+ influx into dendritic spines and GluA1 surface insertion by live imaging. This work will define unexplored fundamental molecular mechanisms of how NE regulates postsynaptic functions. It will elucidate new molecular details that might be affected in neurological diseases such as Alzheimer’s disease, which is at least in part due to dysregulation of CaV1.2 and glutamate receptors by β2AR signaling. NE signaling is also relevant for ADHD and PTSD. The postsynaptic assembly of specific signaling components that control PKA-mediated phosphorylation of AMPARs and CaV1.2 and their functional interactions constitute potentially effective and specific targets for drugs that disrupt some of these interactions while not affecting others (e.g., our peptides DSPL and Pep2 that specifically displace the β2AR from AMPAR but not CaV1.2 and vice versa, respectively EMBO J 35,1330). Page 1
去甲肾上腺素和cAMP的突触后信号传导

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:
    10557151
  • 财政年份:
    2022
  • 资助金额:
    $ 47.14万
  • 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:
    $ 47.14万
  • 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:
    $ 47.14万
  • 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:
    9924426
  • 财政年份:
    2016
  • 资助金额:
    $ 47.14万
  • 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:
    $ 47.14万
  • 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:
    $ 47.14万
  • 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:
    $ 47.14万
  • 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:
    $ 47.14万
  • 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:
    $ 47.14万
  • 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:
    $ 47.14万
  • 项目类别:

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