ArticleThe Journal of biological chemistry2013
Functional selectivity of 6'-guanidinonaltrindole (6'-GNTI) at κ-opioid receptors in striatal neurons.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 83 citations in OpenAlex.
- Innovative Approach Reveals How Receptors Control G Protein State Equilibria.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Triazole 187 is a biased KOR agonist that suppresses itch without sedation and induces anxiolytic-like behaviors in mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- Review
- Recommended Opioid Receptor Tool Compounds: ComparativeACS pharmacology & translational science · 2025Article
- Limitations and potential of κOR biased agonists for pain and itch management.Neuropharmacology · 2024Review
- Synthesis and evaluation of 3,4,5-trisubstituted triazoles as G protein-biased kappa opioid receptor agonists.European journal of medicinal chemistry · 2024Article
- Ubiquitination of GRK2 Is Required for the β-Arrestin-Biased Signaling Pathway of Dopamine D2 Receptors to Activate ERK Kinases.International journal of molecular sciences · 2023Article
- Key differences in regulation of opioid receptors localized to presynaptic terminals compared to somas: Relevance for novel therapeutics.Neuropharmacology · 2023Review
- Angelica Yinzi Alleviates Pruritus-Related Atopic Dermatitis through Skin Repair, Antioxidation, and Balancing PeripheralEvidence-based complementary and alternative medicine : eCAM · 2023Article
- Evaluation of the Intracellular Signaling Activities of κ-Opioid Receptor Agonists, Nalfurafine Analogs; Focusing on the Selectivity of G-Protein- and β-Arrestin-Mediated Pathways.Molecules (Basel, Switzerland) · 2022Article
- Finding the Perfect Fit: Conformational Biosensors to Determine the Efficacy of GPCR Ligands.ACS pharmacology & translational science · 2022Review
- Opioid receptors signaling network.Journal of cell communication and signaling · 2022Article
- Kappa Opioid Receptor Ligands and Pharmacology: Diphenethylamines, a Class of Structurally Distinct, Selective Kappa Opioid Ligands.Handbook of experimental pharmacology · 2022Review
- Agonist-Promoted Phosphorylation and Internalization of the Kappa Opioid Receptor in Mouse Brains: Lack of Connection With Conditioned Place Aversion.Frontiers in pharmacology · 2022Article
- Comprehensive overview of biased pharmacology at the opioid receptors: biased ligands and bias factors.RSC medicinal chemistry · 2021Review
- Multifunctional Enkephalin Analogs with a New Biological Profile: MOR/DOR Agonism and KOR Antagonism.Biomedicines · 2021Article
- Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site.eLife · 2021Article
- Biased signaling in naturally occurring mutations of G protein-coupled receptors associated with diverse human diseases.Biochimica et biophysica acta. Molecular basis of disease · 2021Review
- Development of Diphenethylamines as Selective Kappa Opioid Receptor Ligands and Their Pharmacological Activities.Molecules (Basel, Switzerland) · 2020Review
- Strategies for DevelopingThe Journal of pharmacology and experimental therapeutics · 2020Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.