β-Arrestin-biased signaling mediates memory reconsolidation
β-Arrestin-biased signaling mediates memory reconsolidation
复制标题
β-抑制蛋白偏向信号传导介导记忆重建
DOI：
10.1073/pnas.1421758112
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发表时间：
2015-04-07
影响因子：
11.1
通讯作者：
Ma, Lan
中科院分区：
文献类型：
--
作者：
Liu, Xing;Ma, Li;Ma, Lan
一个长期存在的假说认为，G蛋白偶联信号通路介导β-肾上腺素能神经系统功能，包括学习和记忆。在这里，我们报告，记忆检索（再激活）诱导激活β（1）-肾上腺素能β-arrestin信号在大脑中，刺激ERK信号和蛋白质合成，导致激活后的记忆再稳定。β-Arrestin 2缺陷小鼠在物体识别、Morris水迷宫和可卡因条件位置偏好范例中表现出受损的记忆再巩固。激活后阻断脑β-肾上腺素能Gs蛋白和β-arrestindependent通路可破坏记忆再巩固。出乎意料的是，选择性阻断Gs/cAMP/PKA信号传导，而不是β-抑制蛋白/ERK信号传导的偏向β-肾上腺素能配体不抑制再巩固。此外，β-arrestin 2缺陷小鼠内嗅皮质中β-arrestin 2的表达以G蛋白途径独立的方式拯救β（1）-肾上腺素能ERK信号传导和再巩固。我们证明了β-arrestinbiased信号调节记忆再巩固，并揭示了β-arrestin-biased配体在治疗记忆相关疾病中的潜力。
A long-standing hypothesis posits that a G protein-coupled signaling pathway mediates beta-adrenergic nervous system functions, including learning and memory. Here we report that memory retrieval (reactivation) induces the activation of beta(1)-adrenergic beta-arrestin signaling in the brain, which stimulates ERK signaling and protein synthesis, leading to postreactivation memory restabilization. beta-Arrestin2-deficient mice exhibit impaired memory reconsolidation in object recognition, Morris water maze, and cocaine-conditioned place preference paradigms. Postreactivation blockade of both brain beta-adrenergic Gs protein-and beta-arrestindependent pathways disrupts memory reconsolidation. Unexpectedly, selective blockade of the Gs/cAMP/PKA signaling but not the beta-arrestin/ERK signaling by the biased beta-adrenergic ligands does not inhibit reconsolidation. Moreover, the expression of beta-arrestin2 in the entorhinal cortex of beta-arrestin 2-deficient mice rescues beta(1)-adrenergic ERK signaling and reconsolidation in a G protein pathway-independent manner. We demonstrate that beta-arrestinbiased signaling regulates memory reconsolidation and reveal the potential for beta-arrestin-biased ligands in the treatment of memoryrelated disorders.