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PMID:1840645

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Citation

Van Tol, HH, Bunzow, JR, Guan, HC, Sunahara, RK, Seeman, P, Niznik, HB and Civelli, O (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610-4

Abstract

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 In the management of socially withdrawn and treatment-resistant schizophrenics, clozapine is one of the most favoured antipsychotics because it does not cause tardive dyskinesia.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.

Links

PubMed Online version:10.1038/350610a0

Keywords

Amino Acid Sequence; Animals; Binding, Competitive; Blotting, Northern; Brain/metabolism; Cell Line; Cloning, Molecular; Clozapine/metabolism; Gene Library; Humans; Kinetics; Molecular Sequence Data; Molecular Weight; Neuroblastoma; Organ Specificity; Protein Conformation; RNA, Messenger/genetics; RNA, Messenger/isolation & purification; Rats; Receptors, Dopamine/genetics; Receptors, Dopamine/metabolism; Receptors, Dopamine D2; Receptors, Dopamine D4; Restriction Mapping; Sequence Homology, Nucleic Acid; Transfection

Significance

Annotations

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

HUMAN:DRD4

enables

GO:0001591: dopamine neurotransmitter receptor activity, coupled via Gi/Go

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DRD4

involved_in

GO:0007212: dopamine receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DRD4

enables

GO:0008144: drug binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DRD4

involved_in

GO:0042417: dopamine metabolic process

ECO:0000305: curator inference used in manual assertion

GO:0004952

P

Seeded From UniProt

complete

HUMAN:DRD4

involved_in

GO:0051586: positive regulation of dopamine uptake involved in synaptic transmission

ECO:0000305: curator inference used in manual assertion

GO:0004952

P

Seeded From UniProt

complete


See also

References

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