The amyloid precursor protein modulates alpha(2A)-adrenergic receptor endocytosis and signaling through disrupting arrestin 3 recruitment

Article

关键词: ALPHA(2A) ADRENERGIC-RECEPTOR;    CULTURED SYMPATHETIC NEURONS;    INTERACTING PROTEINS;    COUPLED RECEPTORS;    DENDRITIC SPINES;    DEFICIENT MICE;    KINASE-A;    IN-VITRO;    SPINOPHILIN;    APP;   

DOI  :  10.1096/fj.201700346R

来源: SCIE

【 摘 要 】

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 alpha(2A)-adrenergic receptor (alpha(2A)AR) that occurs at the intracellular domains of both proteins. The APP interaction with alpha(2A)AR is promoted by agonist stimulation and competes with arrestin 3 binding to the receptor. Consequently, the presence of APP attenuates alpha(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 alpha(2A)AR activation. Concomitantly, agonist-induced internalization of alpha(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 alpha(2A)AR in controlling norepinephrine release and response, this novel regulation of alpha(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 alpha(2A)-adrenergic receptor endocytosis and signaling through disrupting arrestin 3 recruitment.

【 授权许可】

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