title: Multiple dopamine D4 receptor variants in the human population.
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.
authors.affiliation: Laboratory for Molecular Neurobiology, Clarke Institute of Psychiatry, Toronto, Ontario, Canada.
authors.forename: H H
authors.initials: HH
authors.lastname: Van Tol
authors.forename: C M
authors.initials: CM
authors.lastname: Wu
authors.forename: H C
authors.initials: HC
authors.lastname: Guan
authors.forename: K
authors.initials: K
authors.lastname: Ohara
authors.forename: J R
authors.initials: JR
authors.lastname: Bunzow
authors.forename: O
authors.initials: O
authors.lastname: Civelli
authors.forename: J
authors.initials: J
authors.lastname: Kennedy
authors.forename: P
authors.initials: P
authors.lastname: Seeman
authors.forename: H B
authors.initials: HB
authors.lastname: Niznik
authors.forename: V
authors.initials: V
authors.lastname: Jovanovic
mesh_terms: D001483:Base Sequence; D001667:Binding, Competitive; D002460:Cell Line; D003024:Clozapine / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification; D004262:DNA Restriction Enzymes; D015870:Gene Expression; D014644:Genetic Variation; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D010902:Pituitary Gland / Q000737:chemistry; D011954:Receptors, Dopamine / Q000235:genetics* / Q000378:metabolism; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D012091:Repetitive Sequences, Nucleic Acid; D013134:Spiperone / Q000378:metabolism; D013378:Substantia Nigra / Q000737:chemistry; D014162:Transfection
chemical_list: C493599:DRD4 protein, human; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D013134:Spiperone; D004247:DNA; D004262:DNA Restriction Enzymes; D003024:Clozapine