Role of APP Interactions with Heterotrimeric G Proteins: Physiological Functions and Pathological Consequences.
Role of APP Interactions with Heterotrimeric G Proteins: Physiological Functions and Pathological Consequences.
复制标题
应用与异三聚体G蛋白相互作用的作用：生理功能和病理后果。
DOI：
10.3389/fnmol.2017.00003
复制
发表时间：
2017
影响因子：
4.8
通讯作者：
Kögel D
中科院分区：
文献类型：
--
作者：
Copenhaver PF;Kögel D
淀粉样前体蛋白（APP）是阿尔茨海默病（AD）中β-淀粉样肽（Aβ）积累的来源，结构分析表明全蛋白类似于跨膜受体。使用重组膜的初步研究表明，APP可以通过其胞质结构域中的进化G蛋白结合基序直接与异源三聚体G蛋白Gαo（而不是其他G蛋白）相互作用。随后在细胞培养中的研究表明，针对APP胞外结构域的抗体可以刺激Gαo活性，推测是模拟内源性APP配体。此外，长期激活野生型APP或过表达突变型APP亚型与家族性AD可能会引起Go依赖性神经毒性反应，而使用人脑样本的生化分析表明，内源性APP-Go相互作用在AD患者中受到干扰。最近，几种G蛋白依赖性途径与APP的生理作用有关，同时有证据表明APP在各种情况下与Gαo在物理和功能上相互作用。在昆虫模型中的工作已经证明，APP直系同源物APPL直接与运动神经元中的Gαo相互作用，从而APPL-Gαo信号传导调节迁移神经元对发育神经系统中遇到的配体的反应。使用培养的哺乳动物神经元和器官型海马脑片制备物的同步研究表明，APP信号转导通过调节PI 3 K/Akt通路转导可溶性sAPPα片段的神经保护作用，提供了整合APP调节的应激和存活反应的机制。值得注意的是，这种作用也被百日咳毒素抑制，表明Gαo/i蛋白的重要作用。出乎意料的是，来自APP的C-末端片段（CTF）也被发现与Gαs相互作用，CTF-Gαs信号可以通过腺苷酸环化酶/PKA依赖性途径促进神经突生长。这些报告提供了一个有趣的观点，G蛋白开关可能会调节APP依赖的反应，在一个上下文依赖的方式。在这篇综述中，我们提供了一个最新的观点的模型，APP发挥了各种作用，作为一个非典型的G蛋白偶联受体在发育和成人神经系统，我们讨论的假设，这些正常功能的中断可能有助于进行性神经病理学，典型的AD。
Following the discovery that the amyloid precursor protein (APP) is the source of β-amyloid peptides (Aβ) that accumulate in Alzheimer’s disease (AD), structural analyses suggested that the holoprotein resembles a transmembrane receptor. Initial studies using reconstituted membranes demonstrated that APP can directly interact with the heterotrimeric G protein Gαo (but not other G proteins) via an evolutionarily G protein-binding motif in its cytoplasmic domain. Subsequent investigations in cell culture showed that antibodies against the extracellular domain of APP could stimulate Gαo activity, presumably mimicking endogenous APP ligands. In addition, chronically activating wild type APP or overexpressing mutant APP isoforms linked with familial AD could provoke Go-dependent neurotoxic responses, while biochemical assays using human brain samples suggested that the endogenous APP-Go interactions are perturbed in AD patients. More recently, several G protein-dependent pathways have been implicated in the physiological roles of APP, coupled with evidence that APP interacts both physically and functionally with Gαo in a variety of contexts. Work in insect models has demonstrated that the APP ortholog APPL directly interacts with Gαo in motile neurons, whereby APPL-Gαo signaling regulates the response of migratory neurons to ligands encountered in the developing nervous system. Concurrent studies using cultured mammalian neurons and organotypic hippocampal slice preparations have shown that APP signaling transduces the neuroprotective effects of soluble sAPPα fragments via modulation of the PI3K/Akt pathway, providing a mechanism for integrating the stress and survival responses regulated by APP. Notably, this effect was also inhibited by pertussis toxin, indicating an essential role for Gαo/i proteins. Unexpectedly, C-terminal fragments (CTFs) derived from APP have also been found to interact with Gαs, whereby CTF-Gαs signaling can promote neurite outgrowth via adenylyl cyclase/PKA-dependent pathways. These reports offer the intriguing perspective that G protein switching might modulate APP-dependent responses in a context-dependent manner. In this review, we provide an up-to-date perspective on the model that APP plays a variety of roles as an atypical G protein-coupled receptor in both the developing and adult nervous system, and we discuss the hypothesis that disruption of these normal functions might contribute to the progressive neuropathologies that typify AD.