Cited by 960Neurotransmitter Receptor Influence on BehaviorSchizophrenia research and treatmentReceptor Mechanisms and Signaling

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Multiple dopamine D4 receptor variants in the human population

Tol, Hubert H. M. Van, Wu, Caren M., Guan, Hong-Chang, Ohara, Koichi, Bunzow, James R., Civelli, Olivier, Kennedy, James, Seeman, Philip, Niznik, Hyman B., Jovanovic, Vera·1992·Nature

DOI 10.1038/358149a0

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Abstract

The dopamine D4 receptor structurally and pharmacologically resembles the dopamine D2 and D3 receptors. Clozapine, an atypical antipsychotic that is relatively free of the adverse effects of drug-induced parkinsonism and tardive dyskinesia, binds to the D4 receptor with an affinity 10 times higher than to the D2 and D3 receptors. This may explain clozapine's atypical properties. Here we report the existence of at least three polymorphic variations in the coding sequence of the human D4 receptor. A 48-base-pair sequence in the putative third cytoplasmic loop of this receptor exists either as a direct-repeat sequence (D4.2), as a fourfold repeat (D4.4) or as a sevenfold repeat (D4.7). Two more variant alleles were detected in humans. Expression of the complementary DNA for the three cloned receptor variants showed different properties for the long form (D4.7) and the shorter forms (D4.2, D4.4) with respect to clozapine and spiperone binding. To our knowledge, this is the first report of a receptor in the catecholamine receptor family that displays polymorphic variation in the human population. Such variation among humans may underlie individual differences in susceptibility to neuropsychiatric disease and in responsiveness to antipsychotic medication.

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Authors: Tol, H. H. M. V., Wu, C. M., Guan, H.-C., Ohara, K., Bunzow, J. R., Civelli, O., Kennedy, J., Seeman, P., Niznik, H. B., & Jovanovic, V.
Affiliations: University of Toronto (CA)
Oregon Health & Science University (US)
ORCID: Civelli, Olivier
Seeman, Philip
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1992-07
Volume: 358
Issue: 6382
Pages: 149-152
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/358149a0
OpenAlex: W2026395566
Cited by: 955
References: 20
Citations by year: 2026: 2 · 2025: 5 · 2024: 10 · 2023: 15 · 2022: 10 · 2021: 14 · 2020: 43 · 2019: 15 · 2018: 7 · 2017: 12 · 2016: 32 · 2015: 34 · 2014: 26 · 2013: 23 · 2012: 35
FWCI: 16.03
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: dopamine D4 receptor, genetic polymorphism, receptor isoforms, spiperone binding, direct repeats, cytoplasmic loop, atypical antipsychotics, individual differences in drug response
MeSH terms: Base Sequence, Binding, Competitive, Cell Line, Clozapine, DNA, DNA Restriction Enzymes, Humans, Introns, Molecular Sequence Data, Pituitary Gland, Receptors, Dopamine, Repetitive Sequences, Nucleic Acid, Spiperone, Substantia Nigra, Transfection, Genetic Variation, Gene Expression, Receptors, Dopamine D2, Receptors, Dopamine D4

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Multiple dopamine D4 receptor variants in the human population

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