biostudies-literatureZhang FThomas Jefferson UniversityNHLBI NIH HHSNIMH NIH HHSNational Institute of Mental HealthNational Institutes of Health4434-4446https://www.ebi.ac.uk/biostudies/studies/S-EPMC5602903biostudies-literatureUnknown31(10)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_2AAR) that occurs at the intracellular domains of both proteins. The APP interaction with α_2AAR is promoted by agonist stimulation and competes with arrestin 3 binding to the receptor. Consequently, the presence of APP attenuates α_2AAR internalization and desensitization, which are arrestin-dependent processes. Furthermore, in neuroblasFASEB journal : official publication of the Federation of American Societies for Experimental BiologyThe amyloid precursor protein modulates α_2A-adrenergic receptor endocytosis and signaling through disrupting arrestin 3 recruitment.PMC5602903R01 HL121206MH081917R21 HL127599R01 MH081917Zhang FGannon MZhou LJiao KWang QChen YfalseThe 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 α_2A-adrenergic receptor (α_2AAR) that occurs at the intracellular domains of both proteins. The APP interaction with α_2AAR is promoted by agonist stimulation and competes with arrestin 3 binding to the receptor. Consequently, the presence of APP attenuates α_2AAR internalization and desensitization, which are arrestin-dependent processes. Furthermore, in neuroblas2017-01-01T00:00:00Z2017 Oct2025-04-05T14:31:20.645Z2019-03-26T23:57:51ZS-EPMC56029032864601810.1096/fj.201700346R10.1096/fj.201700346r