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The amyloid precursor protein modulates α 2A ‐adrenergic receptor endocytosis and signaling through disrupting arrestin 3 recruitment
Author(s) -
Zhang Fang,
Gan Mary,
Chen Yunjia,
Zhou Lufang,
Jiao Kai,
Wang Qin
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700346r
Subject(s) - internalization , arrestin , endocytosis , microbiology and biotechnology , g protein coupled receptor , receptor , amyloid precursor protein , agonist , biology , chemistry , signal transduction , neuroscience , medicine , alzheimer's disease , biochemistry , disease
The amyloid precursor protein (APP) has long been appreciated for its role in Alzheimer's disease (AD) pathology. However, less is known about the physiologic function of APP outside of AD. Particularly, whether and how APP may regulate functions of cell surface receptors, including GPCRs, remains largely unclear. In this study, we identified a novel direct interaction between APP and the α 2A ‐adrenergic receptor (α 2A AR) that occurs at the intracellular domains of both proteins. The APP interaction with α 2A AR is promoted by agonist stimulation and competes with arrestin 3 binding to the receptor. Consequently, the presence of APP attenuates α 2A AR internalization and desensitization, which are arrestin‐dependent processes. Furthermore, in neuroblastoma neuro‐2A cells and primary superior cervical ganglion neurons, where APP is highly expressed, the lack of APP leads to a dramatic increase in plasma membrane recruitment of endogenous arrestin 3 following α 2A AR activation. Concomitantly, agonist‐induced internalization of α 2A AR is significantly enhanced in these neuronal cells. Our study provided the first evidence that APP fine tunes GPCR signaling and trafficking. Given the important role of α 2A AR in controlling norepinephrine release and response, this novel regulation of α 2A AR by APP may have an impact on modulation of noradrenergic activity and sympathetic tone.—Zhang, F., Gannon, M., Chen, Y., Zhou, L., Jiao, K., Wang, Q. The amyloid precursor protein modulates α 2A ‐adrenergic receptor endocytosis and signaling through disrupting arrestin 3 recruitment. FASEB J. 31, 4434–4446 (2017). www.fasebj.org