The ?2-adrenergic receptor (?2AR) is central in normal lung physiology and disease, but key questions about its regulation remain unanswered. Since ?2AR signaling causes airway smooth muscle relaxation, agonists of the receptor are a mainstay therapy for asthma and COPD. Receptor protein down-regulation is a critical mechanism for controlling ?2AR, and works through ubiquitination and subsequent degradation of ?2AR upon prolonged agonist stimulation. This homeostatic mechanism prevents potentially detrimental persistent activation but comes with a price: the efficacy of ?-agonist therapy is often reduced by the very same process. A better understanding of ?2AR degradation would thus benefit both basic receptor biology and translational ?-agonist therapy. Using a unique genome- wide RNA interference (RNAi) screen, we discovered ?-arrestin3, which is encoded by a novel human gene ARRDC3 (arrestin domain containing 3), as a critical new component of the ?2AR degradation machinery. Alpha-arrestin-3 co-localizes and interacts with ?2AR in an agonist-dependent manner. Through a specific interaction, ?-arrestin3 recruits the ubiquitin E3 ligase NEDD4-1 to activated ?2AR to mediate the receptor ubiquitination and subsequent degradation. Building upon these molecular studies, we now propose to examine the function of ?-arrestin3-mediated ?2AR regulation pathway at the physiologic and human biology levels. We hypothesize that ?-arrestin3-mediated ?2AR degradation plays an important physiological role in the lung and that perturbation of the degradation pathway impacts all aspects of functional outcomes of ?2AR signaling. The proposal is to test this hypothesis with three Aims.
In Aim 1 we will determine the role of ?-arrestin3 in regulating the physiological function of ?2AR in airway smooth cells.
Aim 2 will test the role of ?-arrestin3 in regulating the bronchoprotection provided by ?-agonist administration in mice in vivo.
Aim 3 will investigate the association of genetic variations in the ?-arrestin3-mediated ?2AR degradation pathway with bronchodilator response (BDR) in asthma patients. This highly integrative project combines molecular and cellular biology, animal model, and pharmacogenetics and will establish a critical role for ?-arrestin3 in regulating ?2AR functions in the lung. Moreover, the results will lead to a better understanding of the genetic basis of individual ?-agonist responses, and may ultimately contribute to the development of improved and personalized ?-agonist therapy for asthma and other chronic lung diseases.

Public Health Relevance

This proposal studies the mechanism and function of a newly discovered ?2-adrenerigc receptor regulator at cellular, animal model, and human population levels. The results will lead to a better understanding of basic ? 2AR signaling and therapeutic response to ? -agonists, and may ultimately contribute to the development of novel personalized ?-agonist therapy for asthma and other chronic lung diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CVRS-J (03))
Program Officer
Banks-Schlegel, Susan P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Public Health & Prev Medicine
Schools of Public Health
United States
Zip Code
McGeachie, Michael J; Clemmer, George L; Hayete, Boris et al. (2018) Systems biology and in vitro validation identifies family with sequence similarity 129 member A (FAM129A) as an asthma steroid response modulator. J Allergy Clin Immunol 142:1479-1488.e12
Wang, Qiyu; Yu, Jiujiu; Kadungure, Tatenda et al. (2018) ARMMs as a versatile platform for intracellular delivery of macromolecules. Nat Commun 9:960
Panganiban, Ronald A; Sun, Maoyun; Dahlin, Amber et al. (2018) A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis. J Allergy Clin Immunol 142:1469-1478.e2
Zhu, Zhaozhong; Lee, Phil H; Chaffin, Mark D et al. (2018) A genome-wide cross-trait analysis from UK Biobank highlights the shared genetic architecture of asthma and allergic diseases. Nat Genet 50:857-864
Wang, Qiyu; Lu, Quan (2017) Plasma membrane-derived extracellular microvesicles mediate non-canonical intercellular NOTCH signaling. Nat Commun 8:709
Sun, Maoyun; Lu, Quan (2016) MicroRNA regulation of airway smooth muscle function. Biol Chem 397:507-11
Rodosthenous, Rodosthenis S; Coull, Brent A; Lu, Quan et al. (2016) Ambient particulate matter and microRNAs in extracellular vesicles: a pilot study of older individuals. Part Fibre Toxicol 13:13
Himes, Blanca E; Koziol-White, Cynthia; Johnson, Martin et al. (2015) Vitamin D Modulates Expression of the Airway Smooth Muscle Transcriptome in Fatal Asthma. PLoS One 10:e0134057
Himes, Blanca E; Jiang, Xiaofeng; Wagner, Peter et al. (2014) RNA-Seq transcriptome profiling identifies CRISPLD2 as a glucocorticoid responsive gene that modulates cytokine function in airway smooth muscle cells. PLoS One 9:e99625
Hu, Ruoxi; Pan, Wenchi; Fedulov, Alexey V et al. (2014) MicroRNA-10a controls airway smooth muscle cell proliferation via direct targeting of the PI3 kinase pathway. FASEB J 28:2347-57