| First Author | Schmid CL | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 31 | Pages | 22387-98 |
| PubMed ID | 23775075 | Mgi Jnum | J:201919 |
| Mgi Id | MGI:5516163 | Doi | 10.1074/jbc.M113.476234 |
| Citation | Schmid CL, et al. (2013) Functional selectivity of 6'-guanidinonaltrindole (6'-GNTI) at kappa-opioid receptors in striatal neurons. J Biol Chem 288(31):22387-98 |
| abstractText | 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 Galphai/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. |
