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PMID:1319557

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Citation

Van Tol, HH, Wu, CM, Guan, HC, Ohara, K, Bunzow, JR, Civelli, O, Kennedy, J, Seeman, P, Niznik, HB and Jovanovic, V (1992) Multiple dopamine D4 receptor variants in the human population. Nature 358:149-52

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.

Links

PubMed Online version:10.1038/358149a0

Keywords

Base Sequence; Binding, Competitive; Cell Line; Clozapine/metabolism; DNA/chemistry; DNA/isolation & purification; DNA Restriction Enzymes; Gene Expression; Genetic Variation; Humans; Introns; Molecular Sequence Data; Pituitary Gland/chemistry; Receptors, Dopamine/genetics; Receptors, Dopamine/metabolism; Receptors, Dopamine D2; Receptors, Dopamine D4; Repetitive Sequences, Nucleic Acid; Spiperone/metabolism; Substantia Nigra/chemistry; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:DRD4

enables

GO:0008144: drug binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DRD4

enables

GO:0035240: dopamine binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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