PULSe Student Seminar

January 22, 2018
3:30 PM - 4:30 PM
STEW 310


Topic: β-arrestin-biased δ-opioid receptor (δOR) signaling: a novel therapeutic target for anxiety disorders

Presenter: Mee Jung Ko
                  Ph.D. candidate, Department of Medicinal Chemistry and Molecular Pharmacology Integrative Neuroscience Training Group


Anxiety disorders are one of the most common mental disorders in the States affecting approximately 18 % of the population. Although psychoactive drugs and antidepressants are the first-line medications for anxiety disorders, the ubiquitous targets (e.g. GABA receptors and 5-HT receptors) of these drugs give rise to serious side effects such as drowsiness, nausea, and dependence. For this reason, there remains a significant need for discovering novel therapeutic targets with restricted mechanisms of action. Our research has focused on intracellular singaling pathways of a novel target, δ-opioid receptor (δOR). The δOR is a G-protein coupled receptor (GPCR) that has been known to modulate anxiety-like behavior. In our studies, we utilized the concept of ‘biased signaling’ to selectively investigate specific GPCR-mediated signaling pathways such as G-protein or β-arrestin pathways. Based on our previous research, we hypothesized that the β-arrestin-mediated pathways play a key role in δOR- mediated anxiolysis-like behavior. We employed a δOR-selective agonist, SNC80, that strongly promotes β- arrestin recruitment to investigate our hypothesis. Anxiety-like behavior and conditioned fear responses in mice were measured using the elevated plus maze (EPM), the dark-light transition box, and the fear-potentiated startle (FPS) test. We found that SNC80 (20 mg/kg i.p) significantly alleviated anxiety-like behavior and FPS responses in wild-type mice, but the SNC80-mediated anxiolysis-like behavior was ablated in β-arrestin2 knockout mice. In vitro characterization of δOR signaling following SNC80 further revealed that phosphorylation of Mitogen- activated protein kinase 1/2 (ERK1/2) was increased in CHO cells endogenously overexpressing δOR and β- arrestin2. Inhibiton of the ERK1/2 phosphorylation abolished SNC80-mediated anxiolysis-like behavior in wild- type mice, which indicates that the ERK1/2 phosphorylation is required for β-arrestin2-mediated anxiolysis-like behavior. Taken together, we suggest that β-arrestin2-biased signaling at δOR ameliorates anxiety-like behavior through ERK1/2 phosphorylation. Our findings provide novel insight into δOR pharmacology and the development of medicinal interventions for treating anxiety disorders.


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