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Int J Neuropsychopharmacol
2018 Dec 01;2112:1102-1108. doi: 10.1093/ijnp/pyy059.
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The Beta-Arrestin-Biased Dopamine D2 Receptor Ligand, UNC9994, Is a Partial Agonist at G-Protein-Mediated Potassium Channel Activation.
Ågren R
,
Århem P
,
Nilsson J
,
Sahlholm K
.
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Background: Previous evidence suggests that UNC9994 is a beta-arrestin2-selective agonist at the dopamine D2 receptor, lacking ability both to activate and antagonize G protein-dependent signaling. However, this has only been reported by one laboratory using a single assay.
Methods: We used G protein-coupled inward rectifier potassium channel activation in Xenopus oocytes to investigate UNC9994-induced modulation of G protein-dependent signaling at dopamine D2 receptor and dopamine D3 receptor.
Results: At dopamine D2 receptor, UNC9994 induced G protein-coupled inward rectifier potassium channel currents that were 15% of the maximal response to dopamine, with an EC50 of 185 nM. At dopamine D3 receptor, the ligand elicited 89% of the maximal dopamine response with an EC50 of 62 nM. Pertussis toxin abolished G protein-coupled inward rectifier potassium channel activation. Furthermore, UNC9994 antagonized dopamine-induced G protein-coupled inward rectifier potassium channel activation at dopamine D2 receptor.
Conclusions: UNC9994 modulates G protein-coupled inward rectifier potassium channel channel activation via pertussis toxin-sensitive G proteins at dopamine D2 receptor and dopamine D3 receptor. These findings may have implications for the interpretation of data obtained with this ligand.
Figure 1. Actions of UNC9994 on G protein-dependent G protein-coupled inward rectifier (GIRK) signaling elicited via dopamine D2 receptor (D2R) and D3R. (A) Representative current trace recorded in an oocyte coexpressing D2R with Regulators of G protein Signaling (RGS)4 and GIRK1/4 channels, demonstrating GIRK channel activation upon application of increasing concentrations of UNC9994, as indicated. Inset shows the absence of response to 1 and 10 µM UNC9994 in an oocyte coexpressing D2R with RGS4, GIRK1/4, and the catalytic subunit of PTX. (B) Concentration-response curves for GIRK activation by UNC9994 in oocytes expressing D2R or D3R, as indicated, together with RGS4 and GIRK1/4 channels, n=3 to 5 per data point. The mean current amplitude elicited by each concentration of UNC9994 was normalized to the mean amplitude elicited by 1 µM dopamine in separate cells (n=4 for both D2R and D3R). (C) Concentration-response curve for the inhibition of dopamine-induced GIRK activation by UNC9994. Data were obtained from experiments such as that shown in D, n=4 to 6 for each data point. (D) Representative current trace recorded in an oocyte coexpressing D2R with RGS4 and GIRK1/4 channels, showing the inhibition of the GIRK response to 100 nM dopamine by increasing concentrations of UNC9994, as indicated.
Figure 2. UNC9994 acts as a partial agonist at G protein-coupled inward rectifier (GIRK) activation also in the presence of beta-arrestin2. (A) Representative current traces recorded from oocytes coexpressing dopamine D2 receptor (D2R) with GIRK1/4 channels with or without beta-arrestin2, as indicated, demonstrating the impact of beta-arrestin2 coexpression on the time course of the current response to 1 µM dopamine. (B) Ratio between the peak inward current response and the response amplitude at the end of the 240-second application of dopamine. **P<.01, Studentâs t test, n=5 for each group of oocytes. (C) Representative current trace showing GIRK channel activation elicited upon application of 10 µM UNC9994 (UNC) in an oocyte coexpressing D2R with GIRK1/4 channels and beta-arrestin2. (D) Average response to 10 µM UNC9994 as a fraction of the average response to 1 µM dopamine in oocytes coexpressing D2R with GIRK1/4 channels and beta-arrestin2. n=6 for UNC9994; n=5 for dopamine.
Allen,
Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy.
2011, Pubmed
Allen,
Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy.
2011,
Pubmed
Arnsten,
Dopamine's Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders.
2015,
Pubmed
Arnsten,
Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia.
2017,
Pubmed
Beaulieu,
An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior.
2005,
Pubmed
Beaulieu,
The physiology, signaling, and pharmacology of dopamine receptors.
2011,
Pubmed
Dascal,
The Roles of Gβγ and Gα in Gating and Regulation of GIRK Channels.
2015,
Pubmed
Freyberg,
Roles of the Akt/GSK-3 and Wnt signaling pathways in schizophrenia and antipsychotic drug action.
2010,
Pubmed
Grundmann,
Lack of beta-arrestin signaling in the absence of active G proteins.
2018,
Pubmed
Klein Herenbrink,
The role of kinetic context in apparent biased agonism at GPCRs.
2016,
Pubmed
Klewe,
Recruitment of beta-arrestin2 to the dopamine D2 receptor: insights into anti-psychotic and anti-parkinsonian drug receptor signaling.
2008,
Pubmed
Kovoor,
Mu and delta opioid receptors are differentially desensitized by the coexpression of beta-adrenergic receptor kinase 2 and beta-arrestin 2 in xenopus oocytes.
1997,
Pubmed
,
Xenbase
Luedtke,
Comparison of the binding and functional properties of two structurally different D2 dopamine receptor subtype selective compounds.
2012,
Pubmed
Männel,
Structure-Guided Screening for Functionally Selective D2 Dopamine Receptor Ligands from a Virtual Chemical Library.
2017,
Pubmed
Masri,
Antagonism of dopamine D2 receptor/beta-arrestin 2 interaction is a common property of clinically effective antipsychotics.
2008,
Pubmed
McCorvy,
Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs.
2018,
Pubmed
Miyamoto,
Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents.
2012,
Pubmed
Naber,
Aripiprazole: a new atypical antipsychotic with a different pharmacological mechanism.
2004,
Pubmed
Németh,
Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial.
2017,
Pubmed
Onfroy,
G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning.
2017,
Pubmed
Pack,
The dopamine D2 receptor can directly recruit and activate GRK2 without G protein activation.
2018,
Pubmed
Sahlholm,
Antipsychotic-Like Efficacy of Dopamine D2 Receptor-Biased Ligands is Dependent on Adenosine A2A Receptor Expression.
2018,
Pubmed
Sahlholm,
The role of beta-arrestin2 in shaping fMRI BOLD responses to dopaminergic stimulation.
2017,
Pubmed
Sahlholm,
Agonist-specific voltage sensitivity at the dopamine D2S receptor--molecular determinants and relevance to therapeutic ligands.
2011,
Pubmed
,
Xenbase
Scarduzio,
Strength of cholinergic tone dictates the polarity of dopamine D2 receptor modulation of striatal cholinergic interneuron excitability in DYT1 dystonia.
2017,
Pubmed
Urban,
Aripiprazole has functionally selective actions at dopamine D2 receptor-mediated signaling pathways.
2007,
Pubmed
Urs,
Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties.
2016,
Pubmed
Urs,
New Concepts in Dopamine D2 Receptor Biased Signaling and Implications for Schizophrenia Therapy.
2017,
Pubmed
Vivaudou,
Probing the G-protein regulation of GIRK1 and GIRK4, the two subunits of the KACh channel, using functional homomeric mutants.
1997,
Pubmed
,
Xenbase
Zimnisky,
Cariprazine, a dopamine D(3)-receptor-preferring partial agonist, blocks phencyclidine-induced impairments of working memory, attention set-shifting, and recognition memory in the mouse.
2013,
Pubmed
