Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 31, Pages 22387-22398Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.476234
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- National Institutes of Health [R01 DA031927]
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There is considerable evidence to suggest that drug actions at the kappa-opioid receptor (KOR) may represent a means to control pain perception and modulate reward thresholds. As a G protein-coupled receptor (GPCR), the activation of KOR promotes G alpha(i/o) protein coupling and the recruitment of beta-arrestins. It has become increasingly evident that GPCRs can transduce signals that originate independently via G protein pathways and beta-arrestin pathways; the ligand-dependent bifurcation of such signaling is referred to as functional selectivity or signaling bias. Recently, a KOR agonist, 6'-guanidinonaltrindole (6'-GNTI), was shown to display bias toward the activation of G protein-mediated signaling over beta-arrestin2 recruitment. Therefore, we investigated whether such ligand bias was preserved in striatal neurons. Although the reference KOR agonist U69,593 induces the phosphorylation of ERK1/2 and Akt, 6'-GNTI only activates the Akt pathway in striatal neurons. Using pharmacological tools and beta-arrestin2 knock-out mice, we show that KOR-mediated ERK1/2 phosphorylation in striatal neurons requires beta-arrestin2, whereas Akt activation depends upon G protein signaling. These findings reveal a point of KOR signal bifurcation that can be observed in an endogenous neuronal setting and may prove to be an important indicator when developing biased agonists at the KOR.
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