Multiple dopamine D4 receptor variants in the human population

  title={Multiple dopamine D4 receptor variants in the human population},
  author={Hubert H.M. Van Tol and Caren M. Wu and H C Guan and Koichi Ohara and James R. Bunzow and Olivier Civelli and James L. Kennedy and Philip Seeman and Hyman B. Niznik and Vera Jovanovic},
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… 

Polymorphisms of the dopamine D4 receptor and response to antipsychotic drugs

The results of this study suggest that inherited variants of D4 may explain some of the interindividual variation seen in patient response to different classes of antipsychotic medication.

The dopamine D4 receptor in schizophrenia: an update

The overall D2 characteristics, plus the anomalous divergence from these characteristics, make the D4 receptor a highly attractive candidate for the dopamine receptor abnormality of schizophrenia.

Dopamine D4 receptors and development of newer antipsychotic drugs

The therapeutic potential of D4 receptors as a target for developing antipsychotics will be known only when selective D4 receptor antagonists with varying D2/D4 and D4/5‐HT2A ratios are developed and tested in psychiatric patients.

Dopamine D4 Receptors

As novel serotonin-dopamine receptor antagonists with defined pharmacological profiles become available, the careful analysis of the relationship between receptor binding profiles and efficacy will determine the most important receptor targets for improved antipsychotic action without the generation of EPS.

Dopamine D4 receptor variant, D4GLYCINE194, in Africans, but not in Caucasians: no association with schizophrenia.

None of the 147 Caucasians (113 controls; 34 schizophrenics) revealed this variant, termed D4GLYCINE194, which occurs one amino acid away from a serine amino acid which is critical for the attachment of dopamine.

Dopamine D4 receptor variant in Africans, D4valine194glycine, is insensitive to dopamine and clozapine: report of a homozygous individual.

It was found that the D4Valine194Glycine receptor was two orders of magnitude less sensitive to dopamine, clozapine and olanzapine, and the variant receptor was insensitive to guanine nucleotide, indicating the absence of a high-affinity state or functional state.

Analysis of the D4 dopamine receptor gene variant in an Italian schizophrenia kindred.

The genetic linkage study in a large Italian kindred segregating schizophrenia showed significant evidence for exclusion for linkage between schizophrenia and the dopamine D4 receptor gene and the TH gene under the models specified.



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

The cloning of a gene that encodes a dopamine receptor gene that has high homology to the human dopamine D2 and D3 receptor genes is reported, which suggests the existence of other types of dopamine receptors which are more sensitive to clozapine.

Cloning and expression of a rat D2 dopamine receptor cDNA

This receptor has been characterized on the basis of three criteria: the deduced amino-acid sequence which reveals that it is a member of the family of G-protein-coupled receptors; the tissue distribution of the mRNA which parallels that of the D2 dopamine receptor; and the pharmacological profile of mouse fibroblast cells transfected with the cDNA.

The dopamine D2 receptor: two molecular forms generated by alternative splicing.

Results from polymerase chain reactions as well as in situ hybridization revealed that mRNA encoding both receptor forms is present in pituitary and brain of both rat and man, and the two receptor forms are generated by differential splicing possibly to permit coupling to different G proteins.

Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics

The D3 receptor is localized to limbic areas of the brain, which are associated with cognitive, emotional and endocrine functions, and seems to mediate some of the effects of antipsychotic drugs and drugs used against Parkinson's disease.

Cloning of the cDNA and gene for a human D2 dopamine receptor.

A clone encoding a human D2 dopamine receptor was isolated from a pituitary cDNA library and sequenced, and it was shown that the coding sequence is interrupted by six introns and that the additional amino acids present in the human pituitsary receptor are encoded by a single exon of 87 base pairs.

Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine.

In this relatively brief study, the apparently increased comparative risk of agranulocytosis requires that the use of clozapine be limited to selected treatment-resistant patients.

Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy

It is concluded that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of X-LINKED spinal and bulbar muscular atrophy.