Alternative titles; symbols
HGNC Approved Gene Symbol: DRD2
Cytogenetic location: 11q23.2 Genomic coordinates (GRCh38): 11:113,409,605-113,475,398 (from NCBI)
The D2 dopamine receptor is a G protein-coupled receptor located on postsynaptic dopaminergic neurons that is centrally involved in reward-mediating mesocorticolimbic pathways (Neville et al., 2004). The DRD2 gene encodes encodes 2 molecularly distinct isoforms with distinct functions (Usiello et al., 2000). Signaling through dopamine D2 receptors governs physiologic functions related to locomotion, hormone production, and drug abuse. D2 receptors are also known targets of antipsychotic drugs that are used to treat neuropsychiatric disorders such as schizophrenia (181500).
Bunzow et al. (1988) cloned the rat gene for D2 dopamine receptor. Grandy et al. (1989) cloned the human gene from a pituitary cDNA library. The deduced protein sequence is 96% identical to that of the rat receptor with 1 major difference: the human receptor contains an additional 29 amino acids in its putative third cytoplasmic loop. Southern blot analysis demonstrated the presence of only 1 human DRD2 gene.
Chio et al. (1990) and Montmayeur et al. (1991) identified Drd2 isoforms in rat and mouse, respectively.
Grandy et al. (1989) determined that the human DRD2 coding sequence is interrupted by 6 introns. The additional amino acids present in the human receptor relative to that in the rat are encoded by a single exon of 87 basepairs.
Eubanks et al. (1992) found that the DRD2 gene extends over 270 kb and includes an intron of approximately 250 kb separating the putative first exon from the exons encoding the receptor protein.
Somatostatin (182450) and dopamine are 2 major neurotransmitter systems that share a number of structural and functional characteristics. Somatostatin receptors and dopamine receptors are colocalized in neuronal subgroups, and somatostatin is involved in modulating dopamine-mediated control of motor activity. Using photobleaching fluorescence resonance energy transfer (FRET), Rocheville et al. (2000) demonstrated that the receptors SSTR5 (182455) and D2R interact physically through heterooligomerization to create a novel receptor with enhanced functional activity. The neurotransmitter for either receptor promoted heterodimerization, but the presence of both ligands did not produce an additive or synergistic interaction (Milligan, 2000). The results of Rocheville et al. (2000) provided evidence that receptors from different G protein-coupled receptor families interact through oligomerization. Such direct intramembrane association defines a new and more complex level of molecular crosstalk between related G protein-coupled receptor subfamilies.
By a mechanism of alternative splicing, the D2 receptor gene encodes 2 molecularly distinct isoforms, D2S and D2L (Picetti et al., 1997). They are coexpressed in a ratio favoring the long isoform, D2L. D2L differs from D2S by the presence of an additional 29 amino acids within the third intracellular loop. Usiello et al. (2000) demonstrated that these receptors have distinct functions in vivo; D2L acts mainly at postsynaptic sites and D2S serves presynaptic autoreceptor functions. The cataleptic effects of haloperidol are absent in D2L-deficient mice. This suggests that D2L is targeted by haloperidol, with implications for treatment of neuropsychiatric disorders. The absence of D2L reveals that D2S inhibits D1 receptor-mediated functions, uncovering a circuit of signaling interference between dopamine receptors.
Basu et al. (2001) reported that at nontoxic levels, the neurotransmitter dopamine strongly and selectively inhibited the vascular permeabilizing and angiogenic activities of VEGF (192240). Dopamine acted through D2 dopamine receptors to induce endocytosis of VEGF receptor-2 (191306), which is critical for promoting angiogenesis, thereby preventing VEGF binding, receptor phosphorylation, and subsequent signaling steps. The action of dopamine was specific for VEGF and did not affect other mediators of microvascular permeability or endothelial-cell proliferation or migration. Basu et al. (2001) concluded that their results reveal a link between the nervous system and angiogenesis and indicate that dopamine and other D2 receptors might have value in anti-angiogenesis therapy.
Shao et al. (2013) showed that astrocytic DRD2 modulates innate immunity through alpha-B-crystallin (CRYAB; 123590), which is known to suppress inflammation. Shao et al. (2013) demonstrated that knockout mice lacking Drd2 showed remarkable inflammatory response in multiple central nervous system regions and increased the vulnerability of nigral dopaminergic neurons to neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. Drd2-null astrocytes became hyperresponsive to immune stimuli, with a marked reduction in the level of CRYAB. Preferential ablation of Drd2 in astrocytes robustly activated astrocytes in the substantia nigra. Gain- or loss-of-function studies showed that CRYAB is critical for DRD2-mediated modulation of innate immune response in astrocytes. Furthermore, treatment of wildtype mice with the selective DRD2 agonist quinpirole increased resistance of the nigral dopaminergic neurons to MPTP through partial suppression of inflammation. Shao et al. (2013) concluded that their study indicated that astrocytic DRD2 activation normally suppresses neuroinflammation in the central nervous system through a CRYAB-dependent mechanism, and provided a strategy for targeting the astrocyte-mediated innate immune response in the central nervous system during aging and disease.
Using cryoelectron microscopy, Yin et al. (2020) elucidated the structure of an agonist-bound activated human DRD2-inhibitory G protein (see 139310) complex reconstituted into a phospholipid membrane at 3.7-angstrom resolution. The extracellular ligand-binding site of DRD2 was remodeled in response to agonist binding, with conformational changes in extracellular loop-2, transmembrane domain-5 (TM5), TM6, and TM7, propagating to opening of the intracellular Gi-binding site. The structure revealed interactions unique to the membrane-embedded complex, including helix-8 burial in the inner leaflet, ordered lysine and arginine side chains in the membrane interfacial regions, and lipid anchoring of the G protein in the membrane.
Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including DRD2, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development.
Eubanks et al. (1992) prepared a physical map spanning more than 1.5 Mb of chromosome 11q23, which demonstrated that the neural cell adhesion molecule gene (NCAM; 116930) is located 150 kb 3-prime of the DRD2 gene and is transcribed from the same DNA strand. High resolution fluorescence in situ suppression hybridization using cosmid and YAC clones localized these genes between the APOA1 and STMY genes at the interface of 11q22.3 and 11q23.1. In situ hybridization studies showed, furthermore, that the DRD2/NCAM complex resides telomeric to the STMY1 gene and centromeric of the APOA1 gene.
Grandy et al. (1989) mapped the DRD2 gene to the 11q22-q23 junction by in situ hybridization. They had previously found that the gene was on human chromosome 11 by probing DNA from a panel of somatic cell hybrids.
Gelernter et al. (1992) mapped the DRD2 gene in reference to several other loci on 11q by linkage analysis.
Gelernter et al. (1989) found that D11S29, which was previously localized to 11q23, is closely linked to the DRD2 locus; TaqI polymorphisms of both loci were used to demonstrate the close linkage.
In a family with an 11q22.3;9p22 translocation that cosegregated with affective disorder, Smith et al. (1989) found that the translocation breakpoint at 11q22.3 was within 210 kb of the DRD2 gene. The possibility that the affective disorder was related to the break was raised since the dopamine D2 receptor is a major site of action of neuroleptic agents used in the treatment of affective disorders and schizophrenia (181500).
Among 282 pedigrees in the MRC Cytogenetics Registry, Edinburgh, with familial autosomal anomalies, St Clair et al. (1990) found 1 with 23 cases of mental and/or behavioral disorders. Of the 77 family members available for cytogenetic analysis, 34 were found to carry a balanced translocation t(1;11)(q43;q21). Psychiatric diagnoses had been recorded for 16 of the 34 members with the translocation compared with only 5 of the 43 without it. Lod scores (against chance linkage of the translocation with mental illness) were greatest when the mental disorders in the phenotype were restricted to schizophrenia, schizoaffective disorder, recurrent major depression, and adolescent conduct and emotional disorders. St Clair et al. (1990) suggested that the 11q21-q22 region may be the site of gene(s) predisposing to major mental illness.
TaqIA RFLP
Neville et al. (2004) showed that the TaqIA RFLP is located in the ankyrin repeat and kinase domain containing-1 gene (ANKK1; 608774.0001), located downstream of the DRD2 gene in chromosome band 11q23.1.
TaqIA is associated with DRD2 binding in the striatum. Because of its central role in the neuromodulation of appetitive behaviors, the DRD2 gene was scrutinized as having a possible role in susceptibility to alcoholism. Dal Toso et al. (1989), Giros et al. (1989), and Monsma et al. (1989) identified 2 or more isoforms of the D2 dopamine receptor generated by alternative splicing of mRNA. Using a RFLP analysis of the DRD2 gene in the study of DNA from brain tissue of 35 alcoholics and 35 nonalcoholics, Blum et al. (1990) demonstrated an association between the TaqI A1 allele and alcoholism: the presence of the A1 allele of DRD2 correctly classified 77% of alcoholics, and its absence classified 72% of nonalcoholics. The significance of the findings is far from certain. Although the proportion of white and black subjects was indicated, ethnic stratification still might be responsible for the difference. Bolos et al. (1990) investigated this possible association further, using the same D2/TaqI polymorphism used by Blum et al. (1990) and, in addition, a PCR-SSCP polymorphism of the 3-prime noncoding region of the DRD2 gene. In studies of 40 unrelated white alcoholics, 127 racially matched controls, and 2 white pedigrees, they could find no differences in allele frequencies for either polymorphism between alcoholics, subpopulations of alcoholics, or controls. The PCR-SSCP polymorphism provided independent information against linkage at the DRD2 locus.
As a G protein-coupled receptor located on postsynaptic dopaminergic neurons, DRD2 is centrally involved in reward-mediating mesocorticolimbic pathways and, as such, has been the focus of many studies investigating genetic variation associated with addictive behavior. One such polymorphic locus, linked to the DRD2 gene, is a RFLP designated TaqIA. The TaqIA RFLP was implicated in smoking behavior and alcoholism (reviewed by Comings and Blum (2000)), but its importance is somewhat controversial because of nonreplication issues inherent with association studies (Noble, 1998). Functional studies had suggested that the polymorphism is associated with reduced receptor density in the brain (Jonsson et al., 1999; Pohjalainen et al., 1998) but this result was also not universally accepted (Laruelle et al., 1998).
In a study of 884 nonalcoholic Finnish Caucasian males, Hallikainen et al. (2003) found that the self-reported alcohol consumption of the TaqIA homozygous A1/A1 group was 30% and 40% lower than that of the A1/A2 and A2/A2 groups, respectively (p = 0.042).
Li et al. (2004) reported a metaanalysis of 12 studies showing a significantly higher prevalence of the TaqI A1 allele in smokers than in nonsmokers (pooled OR, 1.50; 95% CI, 1.33-1.70; p less than 0.0001).
In 40 pairs of patients with sporadic Parkinson disease, including those with and those without motor fluctuations who were matched for levodopa treatment duration, Wang et al. (2001) found that the DRD2-linked TaqIA polymorphism may be associated with an increased risk for developing motor fluctuations in patients with PD in response to levodopa. Citing previously reported findings, they suggested that the A1A1 genotype may lead to relatively reduced numbers of DRD2 receptors, thus further attenuating the response to already reduced striatal dopamine.
Klein et al. (2007) tested the role of dopamine in monitoring negative action outcomes and feedback-based learning in a neuroimaging study in humans grouped according to the TAQ1A allele (608774.0001). In a probabilistic learning task, A1 allele carriers with reduced dopamine D2 receptor densities learned to avoid actions with negative consequences less efficiently. Their posterior medial frontal cortex, involved in feedback monitoring, responded less to negative feedback than others did. Dynamically changing interactions between the posterior medial frontal cortex and hippocampus found to underlie feedback-based learning were reduced in A1 allele carriers. Based on these findings, Klein et al. (2007) concluded that learning from errors requires dopaminergic signaling. Dopamine D2 receptor reduction seems to decrease sensitivity to negative action consequences, which may explain an increased risk of developing addictive behaviors in A1 allele carriers.
In response to the paper by Klein et al. (2007), Lucht and Rosskopf (2008) noted that the TAQ1A polymorphism actually occurs in the gene encoding the kinase ANKK1 (608774), where it causes a nonconservative amino acid substitution. They suggested caution when considering straightforward reasoning tightly linking TAQ1A variants, dopamine D2 receptor expression, and the observed neuropsychological phenotype in light of the complexities of this genetic locus. In a response, Klein et al. (2008) stated that since their publication, further genetic and pharmacologic studies have bolstered the conclusion that dopamine D2 receptors are essential for performance monitoring and learning. Although the functionally complex polymorphism DRD2-TAQ1A may also affect cellular signaling components, the accumulated evidence supports the notion that their findings were mediated by differential D2 receptor density.
Possible Association with Schizophrenia
Using a family-based study design, Schindler et al. (2002) investigated the association between a functional polymorphism in the promoter region of the DRD2 gene (-141ins/delC) and schizophrenia in a Portuguese population. Analysis of 78 trios revealed evidence for association between the -141insC allele and schizophrenia, using the haplotype relative risk (HRR) method (X2 = 9.30, P = 0.0023). The TDT of 33 informative matings from the Portuguese trios provided evidence for an allelic association and linkage disequilibrium between the insertion allele and schizophrenia (chi square = 8.76, p = 0.0031).
Lencz et al. (2006) examined the response of 61 first-episode schizophrenia patients with reference to 2 promoter region SNPs (241A-G and -141ins/del)C of the DRD2 gene. Patients meeting selection criteria were randomized to receive 16 weeks of treatment with either risperidone or olanzapine. Time until sustained response (2 consecutive ratings without significant positive symptoms) for the rare allele carriers versus wildtype allele was examined using Kaplan-Meier curves. Carriers with the rarer -241A allele exhibited a significantly faster time until response (log-rank = 8.40, df = 1, p less than 0.004) and the -141delC carriers took significantly longer (log-rank = 5.03, df = 1, p less than 0.03) to respond, suggesting that variation in the DRD2 receptor gene can partially explain variation in the timing of clinical response to antipsychotics in the first episode of schizophrenia.
Glatt et al. (2003) noted that there was evidence both supporting and refuting an association between a ser311-to-cys (S311C) polymorphism of the DRD2 gene and schizophrenia. They therefore conducted a metaanalysis of 24 published case-control studies that examined this association, consisting of a total of 3,733 cases and 5,373 controls. The analysis yielded a pooled odds ratio of 1.3 for the cys allele (p = 0.007), suggesting that DRD2 influences susceptibility to schizophrenia. The finding was only detectable, however, in very large sample sets.
Jonsson et al. (2003) conducted a metaanalysis of all published case-control studies comprising a total of 9,152 subjects, which supported the involvement of the cys311 DRD2 allele in the pathogenesis of schizophrenia (chi square = 11.37, df = 1, p less than 0.001; OR 1.43, 95% CI 1.16-1.78). Glatt and Jonsson (2006) used fixed- and random-effects metaanalyses to reanalyze the data used in the metaanalysis of Jonsson et al. (2003). A total of 27 samples, comprising 3,707 schizophrenia patients and 5,363 control subjects were included in the analysis of allelic association, whereas smaller numbers of studies in subjects were included in each of the genotyping association analyses. A significant effect of the cys allele was observed under both fixed-effects (OR = 1.4; P = 0.002) and random-effects (OR = 1.4; P = 0.007) models. Cys/ser heterozygotes were at elevated risk for schizophrenia when compared to ser/ser homozygotes, but cys/cys homozygotes were at no elevated risk relative to heterozygotes.
Gejman et al. (1994) found no mutations in the coding sequence and splice sites of the DRD2 gene that were associated with schizophrenia.
Other Associations
See 604149.0001 for discussion of a possible association between myoclonic dystonia (see 159900) and mutation in the DRD2 gene.
Suarez et al. (1994) tested 4 DRD2 RFLPs that spanned coding regions as well as a 3-prime flanking RFLP in a sample of 88 unrelated Caucasian alcoholics and 89 unrelated race-matched controls. No significant difference for any RFLP frequency between these samples was observed. The results did not support the involvement of the DRD2 region in the etiology of alcoholism. Gejman et al. (1994) found no mutations in the coding sequence and splice sites of the DRD2 gene that were associated with alcoholism.
In a study of 136 subjects with Parkinson disease (PD; 168600), Oliveri et al. (1999) found an association between the 15 allele of a polymorphism of the DRD2 gene and the risk of developing peak-dose dyskinesias in response to levodopa treatment (odds ratio, 0.23; 95% CI, 0.10-0.53).
Devor et al. (1990) and Gelernter et al. (1990) excluded linkage of Tourette syndrome (137580) to the DRD2 gene and to flanking loci on chromosome 11.
Duan et al. (2003) investigated functional effects of 6 naturally occurring synonymous changes in the human DRD2 gene. The 957C-T polymorphism, rather than being silent, altered the predicted mRNA folding, led to a decrease in mRNA stability and translation, and dramatically changed dopamine-induced upregulation of DRD2 expression in transfected CHO cells. The 1101G-A polymorphism did not show an effect by itself but annulled the above effects of 957T in the compound clone 957T/1101A, demonstrating that combinations of synonymous mutations may have functional consequences drastically different from those of each isolated mutation. In addition, 957C-T was found to be in linkage disequilibrium in a European-American population with the -141C ins/del and TaqI 'A' variants, which had been reported to be associated with schizophrenia and alcoholism, respectively. The results called into question assumptions made about synonymous variation in molecular population genetics and gene mapping studies of diseases with complex inheritance, and indicated that synonymous variation can have effects of potential pathophysiologic and pharmacogenetic importance.
Baik et al. (1995) used homologous recombination to generate D2 receptor-deficient mice. Absence of D2 receptors led to animals that were akinetic and bradykinetic in behavioral tests and showed significantly reduced spontaneous movements. The phenotype resembled Parkinson disease. Maldonado et al. (1997) studied the behavior of DRD2 knockout mice and showed that there was a total suppression of rewarding behavior with morphine. In contrast, these animals showed normal responses when food was used as a reward.
Chronic blockade of dopamine D2 receptors, a common mechanism of action for antipsychotic drugs, downregulates D1 receptors (126449) in the prefrontal cortex and, as shown by Castner et al. (2000), produces severe impairments in working memory. These deficits were reversed in monkeys by short-term coadministration of a D1 agonist, ABT431, and this improvement was sustained for more than a year after cessation of D1 treatment. Castner et al. (2000) concluded that pharmacologic modulation of the D1 signaling pathway can produce long-lasting changes in functional circuits underlying working memory. Resetting this pathway by brief exposure to the agonist may provide a valuable strategy for therapeutic intervention in schizophrenia and other dopamine-dysfunctional states.
In rat/mouse neuronal cell lines, Yujnovsky et al. (2006) found that Drd2 mediated stimulation of circadian Clock (601851):Bmal1 (602550) activity and increased expression of the Per1 (602260) gene. The response was mediated by the transcriptional coactivator CREB-binding protein (CREBBP; 600140). Clock:Bmal1-dependent activation and light inducibility of Per1 transcription were drastically dampened in the retinas of Drd2-null mice. The findings suggested a physiologic link between photic input, dopamine signaling, and molecular clock machinery.
Dalley et al. (2007) reported that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine function before drug exposure. Using positron emission tomography, Dalley et al. (2007) demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of dopamine release. Dalley et al. (2007) concluded that their data demonstrated that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.
Schaefer et al. (2010) generated mice lacking Ago2 (EIF2C2; 606229), which plays a significant role in microRNA (miRNA) generation and miRNA-mediated gene silencing, in Drd2-expressing striatum neurons. These mice had normal neuron and brain morphology. Ablation of Ago2 in Drd2-expressing striatum neurons alleviated cocaine addiction, as manifested by reduced motivation to self-administer the drug. Reduced drug dependence was associated with selective downregulation of a set of miRNAs in Ago2-deficient striatum. Comparison of these Ago2-dependent miRNAs with miRNAs enriched and/or upregulated in Drd2-expressing neurons revealed 23 miRNAs likely to play a role in cocaine addiction. Reporter assays showed that these 23 miRNAs regulated genes important for the development of cocaine addiction, including Cdk5r1 (603460) and the transcription factors Fosb (164772) and Mef2d (600663).
This variant, formerly titled MYOCLONUS-DYSTONIA SYNDROME, has been reclassified based on the findings of Klein et al. (2002).
In a family of Welsh-Scottish-German origin in which 8 members had alcohol-responsive myoclonus-dystonia (see 159900), Klein et al. (1999) identified a heterozygous G-to-A transition at the first base of codon 154 of the DRD2 gene, resulting in a val154-to-ile (V154I) substitution. By in vitro functional expression assay, Klein et al. (2000) found that the V154I-mutant protein was similar to wildtype and did not show impaired activity. In the same family, Klein et al. (2002) identified a 5-bp deletion in the SGCE gene (604149.0005) in all 8 affected members. The mutation resulted in a frameshift and premature stop. There were 2 unaffected carriers of both mutations. The contribution of each mutation to the clinical phenotype could not be determined, but the phenotype most likely resulted from the SGCE mutation, as Klein et al. (2000) showed that the V154I DRD2 mutant protein was similar to wildtype and did not show impaired activity in in vitro studies.
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