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

SUBMITTER: Zhang F

PROVIDER: S-EPMC5602903 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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The amyloid precursor protein modulates α2A-adrenergic receptor endocytosis and signaling through disrupting arrestin 3 recruitment.

Zhang Fang F Gannon Mary M Chen Yunjia Y Zhou Lufang L Jiao Kai K Jiao Kai K Wang Qin Q

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20170623 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 α2A-adrenergic receptor (α2AAR) that occurs at the intracellular domains of both prote ...[more]

PMID: 28646018

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Project description:Reperfusion as a therapeutic intervention for acute myocardial infarction-induced cardiac injury itself induces further cardiomyocyte death. ?-arrestin (?arr)-biased ?-adrenergic receptor (?AR) activation promotes survival signaling responses in vitro; thus, we hypothesize that this pathway can mitigate cardiomyocyte death at the time of reperfusion to better preserve function. However, a lack of efficacious ?arr-biased orthosteric small molecules has prevented investigation into whether this pathway relays protection against ischemic injury in vivo. We recently demonstrated that the pepducin ICL1-9, a small lipidated peptide fragment designed from the first intracellular loop of ?2AR, allosterically engaged pro-survival signaling cascades in a ?arr-dependent manner in vitro. Thus, in this study we tested whether ICL1-9 relays cardioprotection against ischemia/reperfusion (I/R)-induced injury in vivo. Methods: Wild-type (WT) C57BL/6, ?2AR knockout (KO), ?arr1KO and ?arr2KO mice received intracardiac injections of either ICL1-9 or a scrambled control pepducin (Scr) at the time of ischemia (30 min) followed by reperfusion for either 24 h, to assess infarct size and cardiomyocyte death, or 4 weeks, to monitor the impact of ICL1-9 on long-term cardiac structure and function. Neonatal rat ventricular myocytes (NRVM) were used to assess the impact of ICL1-9 versus Scr pepducin on cardiomyocyte survival and mitochondrial superoxide formation in response to either serum deprivation or hypoxia/reoxygenation (H/R) in vitro and to investigate the associated mechanism(s). Results: Intramyocardial injection of ICL1-9 at the time of I/R reduced infarct size, cardiomyocyte death and improved cardiac function in a ?2AR- and ?arr-dependent manner, which led to improved contractile function early and less fibrotic remodeling over time. Mechanistically, ICL1-9 attenuated mitochondrial superoxide production and promoted cardiomyocyte survival in a RhoA/ROCK-dependent manner. RhoA activation could be detected in cardiomyocytes and whole heart up to 24 h post-treatment, demonstrating the stability of ICL1-9 effects on ?arr-dependent ?2AR signaling. Conclusion: Pepducin-based allosteric modulation of ?arr-dependent ?2AR signaling represents a novel therapeutic approach to reduce reperfusion-induced cardiac injury and relay long-term cardiac remodeling benefits.

Dataset Information

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

Publications

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

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