Pharm GKB Summary: Dopamine Receptor D2

Overview

Dopamine is a catecholamine neurotransmitter and controls a variety of functions including cognition, emotion, locomotor activity, food intake, and endocrine system regulation in the central nervous system. In the periphery, dopamine modulates cardiovascular and renal functions, hormone secretion, and gastrointestinal motility. Several pathological conditions, such as Parkinson’s disease (PD), schizophrenia, restless leg syndrome, and endocrine tumors, for example, pituitary adenomas have been linked to dysregulation of dopaminergic signal transmission. The dopamine D₂ receptor (DRD2) is one of the five different dopamine receptors that have been identified in humans, and shows high expression in both the pituitary gland and the central nervous system. The dopamine receptors belong to the family of G protein coupled receptors. They are grouped into D₁-like receptors, including DRD1 and DRD5, generally associated with stimulatory functions, and D₂-like receptors, including DRD2, DRD3, and DRD4, generally associated with inhibitory functions. The distinct subfamily of G protein coupled receptors, to which DRD2, DRD3, and DRD4 belong, was derived likely from gene duplication before the vertebrate expansion; these receptors are also known to share similar pharmacological profiles.

In 1989, Grandy et al. cloned and mapped the DRD2 gene to the 11q22–q23 junction by in-situ hybridization. The gene is interrupted by six introns. Alternative splicing of this gene results in short (D2S) and long (D2L) isoforms. The short isoform is also known as D2(415), whereas the long isoform is known as D2(444). The difference between the long and short isoforms is the inclusion of an alternatively spliced exon that accounts for the 29 extra amino acids found in third cytoplasmic loop in the protein structure of the long isoform. D2L is primarily located postsynaptically, whereas D2S functions as a presynaptic autoreceptor. The two isoforms have similar pharmacological characteristics. The length modification of the third cytoplasmatic loop suggests that there may be downstream signaling differences between the two isoforms. Differences in Gi protein subtype preferences and in regulation of receptor internalization were found for D2S and D2L. A third longer isoform was reported in brains from patients who died with psychosis, but this isoform has not been fully characterized. A study, which investigated regulatory polymorphisms in DRD2 gene, showed that the T allele of two highly linked single nucleotide polymorphisms (SNPs) in intron 5, rs2283265 (G > T) and intron 6, rs1076560 (G > T) shift splicing from D2S to D2L.

Many dopamine receptor agonists that bind to the D₂-like family of dopamine receptors are used as antiparkinsonian medications, such as apomorphine, bromocriptine, cabergoline, dihydroergocryptine, lisuride, pergolide, piribedil, pramipexole, ropinirole, and rotigotine [19,20]. Most antipsychotics antagonize the DRD2 as part of their pharmacological profile but also act at a number of other neurotransmitter receptors including other dopamine receptor subtypes, serotonin and histamine receptors [21–23]. First generation or typical antipsychotic drugs such as chlorpromazine and haloperidol cause both antipsychotic actions and many side effects, which are contributed to their high affinity DRD2 antagonism [24]. Side effects of antipsychotics include risk of tardive dyskinesia (TD), extrapyramidal side effects, and hyper-prolactinemia [24]. Olanzapine, quetiapine, and ziprasi-done are second generation or atypical antipsychotics that have a more pronounced serotonin antagonism than dopamine antagonism but still antagonize DRD2 [24]. Risperidone, another second generation antipsychotic, has a more balanced serotonin–dopamine antagonism profile [25]. Aripiprazole [26] and bifeprunox [27] are the newest atypical antipsychotic drugs [28]. Unlike other antipsychotics, aripiprazole and bifeprunox act as partial DRD2 agonists. Aplindore, another partial DRD2 agonist, was originally developed as an antipsychotic and is currently being studied as a potential treatment for PD [28,29]. Kapur and Seeman [30] also postulated a fast dissociation hypothesis based on a study of clozapine and quetiapine toward D2 receptor, and suggested that it is the possible explanation for the low extrapyramidal side effects induced by these two drugs as compared with other atypical and typical antipsychotics.

More than 200 polymorphisms have been identified in the DNA encompassing the genomic sequence of this gene; most are in the introns and the downstream flanking region [7,15,31–36], but some are in the coding [37] and the upstream promoter regions [38]. Allele frequencies of a number of these polymorphisms have been determined in different populations (http://alfred.med.yale.edu/alfred/recordinfo.asp?condition=loci.locus_uid=`LO000168P). Variants of the DRD2 gene have been associated with alcoholism and other addictive disorders such as cocaine, nicotine and opioid dependence, mood disorders, schizophrenia, and movement disorders, reviewed in [39]. DRD2 variants are not only relevant to disease susceptibility but also have been associated with the pharmacogenetics of several antipsychotics [40]. In addition, DRD2 is among the several candidate genes that have been reported to be associated with the efficacy of bupropion and nicotine replacement therapy (NRT) for smoking cessation [41]. The four SNPs, discussed in more detail in the important variant section below, are the most commonly investigated SNPs in the DRD2 gene.

Online content for the DRD2 gene (PA27478) and very important pharmacogene summary information is available at http://www.pharmgkb.org/search/annotatedGene/drd2.