The amyloid precursor protein modulates α _2A ‐adrenergic receptor endocytosis and signaling through disrupting arrestin 3 recruitment

Abstract

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

β-Arrestin Based Receptor Signaling Paradigms: Potential Therapeutic Targets for Complex Age-Related Disorders

“…The α 2A AR plays an important role in controlling norepinephrine release and response. This discovery that APP can affect α 2A AR internalization may have an impact on modulation of noradrenergic activity and sympathetic tone, but also affecting pain perception and decreasing epileptogenesis and anxiety ( Hein, 2006 ; Masse et al, 2006 ; Gyires et al, 2009 ; Zhang et al, 2017 ). The noradrenergic system regulates arousal, learning and memory, which has also been implicated in regulating neuroinflammation ( Ardestani et al, 2017 ).…”

“…Proteins being targeted for drug development are amyloid β, γ-secretase and the amyloid β precursor protein (APP). The aberrant processing of these proteins has been identified as a hallmark of AD development ( Martin et al, 2013 ; Thathiah et al, 2013 ; Zhang et al, 2017 ).…”

“… Zhang et al (2017) investigated the association of APP with GPCRs – they found that APP interacted with α 2A AR. The association between these two proteins is promoted by agonist stimulation, but competes with β-arrestin2 binding to the receptor and thus negatively affects receptor arrestin-dependent internalization and desensitization ( Zhang et al, 2017 ). The α 2A AR plays an important role in controlling norepinephrine release and response.…”

“…The noradrenergic system regulates arousal, learning and memory, which has also been implicated in regulating neuroinflammation ( Ardestani et al, 2017 ). This loss of the noradrenergic tone may underlie AD progression at many levels ( Ardestani et al, 2017 ; Zhang et al, 2017 ), and has further also been investigated by Ardestani et al (2017) in the 5XFAD mouse model of AD. This research group used a partial agonist of the β1AR, Xamoterol, which restores the behavioral deficits of AD mouse models ( Ardestani et al, 2017 ).…”

Importance of GPCR-Mediated Microglial Activation in Alzheimer’s Disease

“…In recent times, the α 2A -adrenergic receptor has been reported to modulate a novel role in norepinephrine release and response control by APP. APP has been found to disrupt the recruitment of arrestin 3, which modulates α 2A -adrenergic endocytosis (Zhang et al, 2017 ). Moreover, the α 2A -adrenergic receptor has been reported to play a crucial role in dexmedetomidine (DMED)-induced improvement in systemic inflammation (SI)-induced cognitive dysfunction.…”