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Multiple dopamine D4 receptor variants in the human population

Nature volume 358, pages 149–152 (1992)Cite this article

Abstract

THE dopamine D4 receptor structurally and pharmacologically resembles the dopamine D2 and D3 receptors1–5. Clozapine, an atypical antipsychotic that is relatively free of the adverse effects of drug-induced parkinsonism and tardive dyskinesia6,7, binds to the D4 receptor with an affinity 10 times higher than to the D2 and D3 receptors1. 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 and Affiliations

  1. Laboratory for Molecular Neurobiology, Clarke Institute of Psychiatry, 250 College Street, Toronto, Ontario, M5T1R8, Canada

    Hubert H. M. Van Tol, Caren M. Wu, Hong-Chang Guan, Koichi Ohara, Hyman B. Niznik & Vera Jovanovic

  2. Laboratory for Molecular Genetics, Clarke Institute of Psychiatry, 250 College Street, Toronto, Ontario, M5T1R8, Canada

    James Kennedy

  3. Departments of Pharmacology and Psychiatry, University of Toronto, Medical Sciences Building, Toronto, Ontario, M5S 1A8, Canada

    Hubert H. M. Van Tol, Caren M. Wu, Hong-Chang Guan, Koichi Ohara, Philip Seeman, Hyman B. Niznik & Vera Jovanovic

  4. Vollum Institute for Advanced Biomedical Research, Department of Cell Biology and Anatomy, Oregon Health Sciences University, Portland, Oregon, 97201, USA

    James R. Bunzow & Olivier Civelli

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  1. Hubert H. M. Van Tol
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Tol, H., Wu, C., Guan, HC. et al. Multiple dopamine D4 receptor variants in the human population. Nature 358, 149–152 (1992). https://doi.org/10.1038/358149a0

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