Novel GαS-protein signaling associated with membrane-tethered amyloid precursor protein intracellular domain.
Novel GαS-protein signaling associated with membrane-tethered amyloid precursor protein intracellular domain.
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DOI：
10.1523/jneurosci.5433-11.2012
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发表时间：
2012-02-01
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通讯作者：
Parent AT
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作者：
Deyts C;Vetrivel KS;Das S;Shepherd YM;Dupré DJ;Thinakaran G;Parent AT
许多生理功能，包括作为细胞表面受体的作用，已归因于阿尔茨海默病相关淀粉样前体蛋白（APP）。然而，APP在神经元中介导的胞内信号传导的详细分析一直缺乏。在这里，我们表征了与膜结合的APP c端片段相关的内在信号，这些片段是在APP外结构域被α-或β-分泌酶切割释放后产生的。我们发现，APP c端片段的积累或膜系APP胞内结构域的表达可导致PKA的腺苷酸环化酶依赖性激活和GSK3β信号级联的抑制，并增强大鼠永生化海马神经元、小鼠原代皮质神经元和小鼠神经母细胞瘤的轴突树突化。我们发现了APP胞内结构域BBXXB基序与异三聚体g蛋白亚基GαS之间的相互作用，并证明了GαS与腺苷酸环化酶的偶联介导了膜系APP胞内结构域诱导的神经突生长。我们的研究提供了明确的证据，证明APP胞内结构域可以通过其膜关联在调节神经突生长中发挥非转录作用。本研究发现的膜结合APP c端片段与GαS信号的新功能偶联可能影响突触可塑性和记忆形成等多种脑功能。
Numerous physiological functions, including a role as a cell surface receptor, have been ascribed to Alzheimer’s disease-associated amyloid precursor protein (APP). However, detailed analysis of intracellular signaling mediated by APP in neurons has been lacking. Here, we characterized intrinsic signaling associated with membrane-bound APP C-terminal fragments, which are generated following APP ectodomain release by α- or β-secretase cleavage. We found that accumulation of APP C-terminal fragments or expression of membrane-tethered APP intracellular domain results in adenylate cyclase-dependent activation of PKA and inhibition of GSK3β signaling cascades, and enhancement of axodendritic arborization in rat immortalized hippocampal neurons, mouse primary cortical neurons and mouse neuroblastoma. We discovered an interaction between BBXXB motif of APP intracellular domain and the heterotrimeric G-protein subunit GαS, and demonstrate that GαS coupling to adenylate cyclase mediates membrane-tethered APP intracellular domain-induced neurite outgrowth. Our study provides clear evidence that APP intracellular domain can have a non-transcriptional role in regulating neurite outgrowth through its membrane association. The novel functional coupling of membrane-bound APP C-terminal fragments with GαS signaling identified in this study could impact several brain functions such as synaptic plasticity and memory formation.