The amyloid precursor protein modulates α 2A -adrenergic receptor endocytosis and signaling through disrupting arrestin 3 recruitment.

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 α2A -adrenergic receptor (α2A AR) that occurs at the intracellular domains of both proteins. The APP interaction with α2A AR is promoted by agonist stimulation and competes with arrestin 3 binding to the receptor. Consequently, the presence of APP attenuates α2A 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 α2A AR activation. Concomitantly, agonist-induced internalization of α2A 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 α2A AR in controlling norepinephrine release and response, this novel regulation of α2A 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 α2A -adrenergic receptor endocytosis and signaling through disrupting arrestin 3 recruitment.