Dopamine receptor D4

The dopamine receptor D4 is a G protein-coupled receptor encoded by the gene. As with other dopamine receptor subtypes, the D4 receptor is activated by the neurotransmitter dopamine. It is also a target for drugs which treat schizophrenia and Parkinson disease. The D4 receptor is considered to be D2-like in which the activated receptor inhibits the enzyme adenylyl cyclase, thereby reducing the intracellular concentration of the second messenger cyclic AMP.

Polymorphism
This gene contains a polymorphic number (2-10 copies) of tandem 48 nt repeats where the 4 repeat (4R) is the most commonly expressed while 2R and 7R are less common. 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, or more specifically the 7 repeat (7R) has been loosely linked to a susceptibility for developing ADHD and other psychological traits and disorders, like autism.

The receptor expressed by the D4DR gene is responsible in part for detecting the neurotransmitter dopamine which mediates (among other things) pleasure and emotion. The 7 repeat (7R) elongated copy of this gene appears to react less strongly to dopamine molecules.

Novelty seeking
In two studies published in Nature Genetics, subjects filled out personality questionnaires and had blood taken for genetic analysis. The scientists found that those whose answers showed them to be exploratory and excitable &mdash; two hallmarks of novelty-seeking &mdash; also possessed a longer 7 repeat (7R) version of D4DR, compared with those who are more reserved and reflective. A few other studies have replicated these results (including two done in Japan) but at least one has found no such correlation. In any case, thrill-seeking behavior is probably mediated by several genes, and the variance attributable to D4DR by itself is not particularly large.

Ligands



 * WAY-100635, potent full agonist, with 5-HT1A antagonistic component
 * A-412997, full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels
 * FAUC 316, partial agonist, > 8600-fold selective over other dopamine receptor subtypes
 * FAUC 299, partial agonist
 * FAUC 213, antagonist
 * FAUC F41, inverse agonist, subtype selectivity of more than 3 orders of magnitude over D2 and D3