Cloning of the gene for a human dopamine D4 receptor with high affinity for antipsychotic clozapine

• Published in: Nature (London) Vol. 350; no. 6319; pp. 610 - 614
• Main Authors: VAN TOL, H. H. M, BUNZOW, J. R, HONG-CHANG GUAN, SUNAHARA, R. K, SEEMAN, P, NIZNIK, H. B, CIVELLI, O
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 18.04.1991
• Subjects: Amino Acid Sequence; Animals; Binding, Competitive; Biological and medical sciences; Blotting, Northern; Brain - metabolism; Cell Line; Cell receptors; Cell structures and functions; Cloning, Molecular; Clozapine - metabolism; Fundamental and applied biological sciences. Psychology; Gene Library; Humans; Kinetics; Molecular and cellular biology; Molecular Sequence Data; Molecular Weight; Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine); Neuroblastoma; Organ Specificity; Protein Conformation; Rats; Receptors, Dopamine - genetics; Receptors, Dopamine - metabolism; Receptors, Dopamine D2; Receptors, Dopamine D4; Restriction Mapping; RNA, Messenger - genetics; RNA, Messenger - isolation & purification; Sequence Homology, Nucleic Acid; Transfection; Human; Gene; Nucleotide sequence; Dopamine receptor; Restriction map; Affinity; Antipsychotic; Pharmacology; Molecular cloning; Aminoacid sequence
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/350610a0

Dopamine receptors belong to the family of G protein-coupled receptors. On the basis of the homology between these receptors, three different dopamine receptors (D1, D2, D3) have been cloned. Dopamine receptors are primary targets for drugs used in the treatment of psychomotor disorders such as Parkinson's disease and schizophrenia. In the management of socially withdrawn and treatment-resistant schizophrenics, clozapine is one of the most favoured antipsychotics because it does not cause tardive dyskinesia. Clozapine, however, has dissociation constants for binding to D2 and D3 that are 4 to 30 times the therapeutic free concentration of clozapine in plasma water. This observation suggests the existence of other types of dopamine receptors which are more sensitive to clozapine. Here we report the cloning of a gene that encodes such a receptor (D4). The D4 receptor gene has high homology to the human dopamine D2 and D3 receptor genes. The pharmacological characteristics of this receptor resembles that of the D2 and D3 receptors, but its affinity for clozapine is one order of magnitude higher. Recognition and characterization of this clozapine neuroleptic site may prove useful in the design of new types of drugs.