Bioinformatics Research Laboratory, IBI Biosolutions Pvt. Ltd. India
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The DB-DRD4
Database Project |
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Dopamine receptor D4 (DRD4)
The dopamine receptor D4 (DRD4) is a 7-transmembrane G-protein-coupled dopamine receptor encoded by the DRD4 gene, found in the limbic system, frontal cortex, and other areas of the brain but is expressed at high levels in the prefrontal cortex, that is, a region of the brain associated with cognitive abilities. The D4 is considered to be "D2-like". The DRD4 gene is located on chromosome 11p15.5, and has four exons. The D4 receptor is believed to play a role in higher brain functions, such as affection and personality, and is a candidate gene for several behavioral disorders.The D4 subtype dopamine receptor inhibits adenylyl cyclase. It is also a target for drugs which treat schizophrenia and Parkinson disease.
Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder, and the personality trait of novelty seeking. Particularly, a specific allele (known as the 'DRD4 long' variant) has been loosely linked to a susceptibility for developing ADHDand other psychological traits and disorders, like autism.The D4 receptor binds the antipsychotic drug clozapine more efficiently than do other dopamine receptors, and evidence suggests that the number of D4 receptor molecules may be elevated in schizophrenics as compared with other individuals. The gene coding for the dopamine D4 receptor (DRD4) is highly polymorphic in humans, exhibiting at least 25 alleles.
The coding region of Exon 1 contains a polymorphic 12 bp (4 amino acid) tandem repeat with three alleles in humans, a 13bp deletion polymorphic in Europeans, a rare 21 bp deletion, and a rare nonsynonymous transversion in codon 11. The 13 bp and the 21 bp deletions presumably result in nonfunctional proteins. Of the exon 1 polymorphisms, only the 12 bp repeat is polymorphic worldwide. This polymorphism consists of a 12 bp unit present once, twice, or rarely thrice. The resulting four amino acid duplication (GASA) occurs near the junction of the extracellular domain of the protein and the first transmembrane domain. Exon one of DRD4 codes for the extracellular amino terminus domain and the first two transmembrane domains. The extracellular domain has been shown to be functionally important for agonist binding and signal transduction.
The DRD4 dopamine receptor is uniquely characterized by a 48 bp repeating segment within the coding region, located in Exon III. Different DRD4 alleles are produced by the presence of additional 48 bp repeats, each of which adds 16 amino acids to the length of the 3rd intracytoplasmic loop of the receptor. The DRD4 receptor is therefore an intriguing candidate gene for behaviors which are influenced by dopamine function. In several human populations, DRD4 alleles with 2-8 and 10 repeats have previously been identified, and the 4 and 7 repeat alleles are the most abundant. The degree of DRD4 polymorphism and which DRD4 alleles were present both showed considerable variation across primate species. In contrast to the human, rhesus macaque monkeys were monomorphic. The 4 and 7 repeat alleles, highly abundant in the human, may not be present in certain other primates. For example, the four spider monkeys we studied showed the 7, 8 and 9 repeat length alleles and the only gibbon we analyzed was homozygous for the 9 repeat allele (thus far not observed in the human). Genotyping of other primate species and sequencing of the individual DRD4 repeat alleles in different species may help us determine the ancestral DRD4 repeat length and identify connections between DRD4 genotype and phenotype.
