Cited by 107Receptor Mechanisms and SignalingHeat shock proteins researchNeurotransmitter Receptor Influence on Behavior

Folding Efficiency Is Rate-limiting in Dopamine D4 Receptor Biogenesis

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Van Craenenbroeck, Kathleen, Clark, Stewart D., Cox, Michael J., Oak, James N., Liu, Fang, Van Tol, Hubert H.M.·2005·Journal of Biological Chemistry

Abstract

Dopamine receptors are G protein-coupled receptors that are critically involved in locomotion, reward, and cognitive processes. The D2 class of dopamine receptors (DRD2, -3, and -4) is the target for antipsychotic medication. DRD4 has been implicated in cognition, and genetic studies have found an association between a highly polymorphic repeat sequence in the human DRD4 coding region and attention deficit hyperactivity disorder. Using DRD4 as a model, we show that antipsychotics can function as potent pharmacological chaperones up-regulating receptor expression and can also rescue a non-functional DRD4 folding mutant. This chaperone-mediated up-regulation involves reduced degradation by the 26 S proteasome; likely via the stabilization of newly synthesized receptor in the endoplasmic reticulum. Dopamine itself can function as a chaperone when shuttled into the cell by means of the dopamine transporter. Furthermore, different repeat variants of DRD4 display differential sensitivity to this chaperone effect. These data suggest that folding efficiency may be rate-limiting for dopamine receptor biogenesis and that this efficiency differs between receptor variants. Consequently, the clinical profile of dopaminergic ligands, including antipsychotics, may include their ability to serve as pharmacological chaperones.

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Crossref · 10.1074/jbc.m414043200

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52 of 52 references verified0 citation errors · 0 not checkable

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  • Functional significance of the DRD4 48-bp exon III VNTR polymorphism has been demonstrated.

    “Functional significance of this polymorphism has been demonstrated [70–75].”

    From Genetics of child aggression, a systematic review (2024) · cites this paper as [74]

  • The 7 R DRD4 allele reduces in-vitro DRD4 expression and is less likely to form heterodimers with the dopamine D2 receptor, while the 4 R allele appears less responsive to quinpirole-mediated DRD4 upregulation.

    “The 7 R has been shown to reduce in-vitro DRD4 expression [73] and to be less likely to form heterodimers with the dopamine D2 receptor [76], while the 4 R allele appears to be less responsive to quinpirole-mediated DRD4 upregulation [74].”

    From Genetics of child aggression, a systematic review (2024) · cites this paper as [74]

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Authors
Van Craenenbroeck, K., Clark, S. D., Cox, M. J., Oak, J. N., Liu, F., & Van Tol, H. H. M.
Affiliations
Centre for Addiction and Mental Health (CA)
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2005-05
Volume
280
Issue
19
Pages
19350-19357
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2155062549
Cited by
107
References
52
Citations by year
2026: 1 · 2024: 2 · 2022: 1 · 2020: 5 · 2019: 2 · 2018: 3 · 2017: 5 · 2016: 2 · 2015: 8 · 2014: 7 · 2013: 8 · 2012: 9
FWCI
3.14
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
dopamine D4 receptor, DRD4, receptor biogenesis, pharmacological chaperones, antipsychotic drugs, 26S proteasome degradation, endoplasmic reticulum, dopamine transporter, attention deficit hyperactivity disorder, G protein-coupled receptors, receptor expression
MeSH terms
Animals, Cell Line, DNA, Dopamine, Dose-Response Relationship, Drug, Endoplasmic Reticulum, Glycosylation, Cricetinae, Humans, Ligands, Microscopy, Fluorescence, Mutation, Polymorphism, Genetic, Time Factors, Antipsychotic Agents, Transcription, Genetic, Protein Biosynthesis, Blotting, Northern, Blotting, Western, Up-Regulation, CHO Cells, Protein Structure, Tertiary, Receptors, Dopamine D2, Protein Folding, Microscopy, Confocal, Molecular Chaperones, Proteasome Endopeptidase Complex, Receptors, Dopamine D4

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