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Cited by 91Receptor Mechanisms and SignalingNeurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology Research

Elucidation of G-protein and β-arrestin functional selectivity at the dopamine D2 receptor

Open access
Peterson, Sean M., Pack, Thomas F., Wilkins, Angela D., Urs, Nikhil M., Urban, Daniel J., Bass, Caroline E., Lichtarge, Olivier, Caron, Marc G.·2015·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1502742112PMC PMC4460444
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Abstract

Significance: The dopamine D2 receptor (D 2 R), a G protein-coupled receptor, can initiate signaling events through both activation of G proteins and interactions with β-arrestins. To begin to understand the contribution of these events in the physiology of the dopamine system, D 2 R was mutated to be functionally selective for each signaling pathway. The engineered receptors are functional in vitro and in vivo. Furthermore, both functions are essentially dissociable and mediate different physiological and pharmacological responses. These tools provide an additional but previously unavailable approach to elucidate the role of biased signaling in the multiple physiological actions of the dopamine system.

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  • PKC activation decreases DAT1, NET1 and SERT cell surface expression, intensifying the direct blockage of monoamine transporters by LDX and improving the neurotransmission imbalance in ADHD.

    “This PKC activation decreases DAT1 [181], NET1 [182] and SERT [183] cell surface expression, intensifying the direct blockage of monoamine transporters by LDX and improving the neurotransmission imbalance in ADHD.”

    From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [181]

    Citation [182] is attached to the claim that PKC activation decreases NET1 cell-surface expression. The Results passage describes cell-surface internalization of engineered dopamine D2 receptors, not NET1. Searches for PKC, NET1, and norepinephrine-transporter internalization found no passage addressing that claim; the downstream claims about LDX and ADHD are likewise not established by this copy. (LLM, conf=0.76)

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Cited by

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Authors
Peterson, S. M., Pack, T. F., Wilkins, A. D., Urs, N. M., Urban, D. J., Bass, C. E., Lichtarge, O., & Caron, M. G.
Affiliations
  • Departments of aCell Biology,
  • Baylor College of Medicine (US)
  • University at Buffalo, State University of New York (US)
  • Duke University (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2015-05-11
Volume
112
Issue
22
Pages
7097-7102
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1502742112
PMC
PMC4460444
OpenAlex
W1488100833
Cited by
91
References
2
Citations by year
2026: 6 · 2025: 6 · 2024: 2 · 2023: 12 · 2022: 6 · 2021: 4 · 2020: 6 · 2019: 7 · 2018: 14 · 2017: 12 · 2016: 9 · 2015: 7
FWCI
6.08
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/misc/userlicense.xhtml (vor, 184 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • HHS | NIH | National Institute of Mental Health (5R37MH073853)
  • HHS | NIH | National Institute on Drug Abuse (K01DA024763)
  • HHS | NIH | National Institute of General Medical Sciences (GM066099, GM079656)
  • NSF | BIO | Division of Biological Infrastructure (DBI-1356569)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
dopamine D2 receptor, G protein signaling, β-arrestin signaling, functional selectivity, biased agonists, evolutionary trace, MAPK signaling, amphetamine-induced locomotion, schizophrenia, receptor mutants
MeSH terms
beta-Arrestins, Animals, Corpus Striatum, Crystallography, Humans, Models, Molecular, Neurons, Protein Conformation, Regression Analysis, Mutagenesis, Receptors, Dopamine D2, GTP-Binding Proteins, Arrestins, MAP Kinase Signaling System, Mice, HEK293 Cells

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