Functional selectivity of 6'-guanidinonaltrindole (6'-GNTI) at κ-opioid receptors in striatal neurons.

TitleFunctional selectivity of 6'-guanidinonaltrindole (6'-GNTI) at κ-opioid receptors in striatal neurons.
Publication TypeJournal Article
Year of Publication2013
AuthorsSchmid CL, Streicher JM, Groer CE, Munro TA, Zhou L, Bohn LM
JournalJ Biol Chem
Date Published2013 Aug 02
KeywordsAnimals, CHO Cells, Corpus Striatum, Cricetinae, Cricetulus, Guanidines, Male, MAP Kinase Signaling System, Mice, Naltrexone, Neurons, Phosphorylation, Receptors, Opioid, kappa

There is considerable evidence to suggest that drug actions at the κ-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 Gαi/o protein coupling and the recruitment of β-arrestins. It has become increasingly evident that GPCRs can transduce signals that originate independently via G protein pathways and β-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 β-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 β-arrestin2 knock-out mice, we show that KOR-mediated ERK1/2 phosphorylation in striatal neurons requires β-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.

Alternate JournalJ. Biol. Chem.
PubMed ID23775075
PubMed Central IDPMC3829329
Grant ListR01 DA031927 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
John M. Streicher, PhD