title: Functional selectivity of 6'-guanidinonaltrindole (6'-GNTI) at κ-opioid receptors in striatal neurons.
abstract: 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.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.
authors.forename: Cullen L
authors.initials: CL
authors.lastname: Schmid
authors.forename: John M
authors.initials: JM
authors.lastname: Streicher
authors.forename: Chad E
authors.initials: CE
authors.lastname: Groer
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Munro
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.forename: Laura M
authors.initials: LM
authors.lastname: Bohn
mesh_terms: D000818:Animals; D016466:CHO Cells; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006146:Guanidines / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D017473:Receptors, Opioid, kappa / Q000187:drug effects*
chemical_list: C503316:6'-guanidinonaltrindole; D006146:Guanidines; D017473:Receptors, Opioid, kappa; D009271:Naltrexone
keywords: Arrestin; Brain; Drug Screening; G Protein-coupled Receptors (GPCR); Gene Knockout; MAP Kinases (MAPKs); Neurons; Opiate Opioid; Receptor Endocytosis; κ-Opioid Receptor