PT  - JOURNAL ARTICLE
AU  - Mee Jung Ko
AU  - Terrance Chiang
AU  - Arbaaz M. Mukadam
AU  - Grace E. Mulia
AU  - Anna M. Gutridge
AU  - Julia A. Chester
AU  - Richard M. van Rijn
TI  - β-arrestin-dependent ERK signaling positively correlates with reduced anxiety-like and conditioned fear-related behavior in mice
AID  - 10.1101/790568
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 790568
4099  - http://biorxiv.org/content/early/2019/10/02/790568.short
4100  - http://biorxiv.org/content/early/2019/10/02/790568.full
AB  - Exposure to anxiety- or fear-invoking stimuli initiate a convergence of executive actions orchestrated by multiple proteins and neurotransmitters across the brain. Dozens of G protein-coupled receptors (GPCRs) have been linked to regulation of fear and anxiety. GPCR signaling involves canonical G protein pathways but may also engage downstream kinases and effectors through β-arrestin scaffolds. Here, we investigate whether β-arrestin signaling is critical for the emotional regulation of anxiety-like and fear-related behavior. Using the δ-opioid receptor (δOR) as a model GPCR, we found that β-arrestin 2-dependent activation of extracellular signal–regulated kinases (ERK1/2) in the dorsal hippocampus and the amygdala are critical for δOR-induced anxiolytic-like effects. In contrast, G protein-mediated δOR signaling was associated with decreased ERK1/2 activity and increased fear-related behavior. Our results also suggest a potential contribution of β-arrestin 1 in fear-reducing effects. Overall, our findings highlight the significance of non-canonical β-arrestin signaling in the regulation of emotions.