Affinage

DRD2

D(2) dopamine receptor · UniProt P14416

Length
443 aa
Mass
50.6 kDa
Annotated
2026-06-09
100 papers in source corpus 26 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DRD2 is a Gi/o-coupled dopamine receptor that controls striatal, hippocampal, and extra-neuronal signaling through parallel G-protein and β-arrestin pathways, and through dynamic assembly into heteroreceptor complexes (PMID:29068002, PMID:29632174). In indirect-pathway medium spiny neurons it engages both Gαi/o and β-arrestin arms, with distinct behaviors (antipsychotic-sensitive metabolic signaling and shredding via G-protein; locomotion and rearing requiring coordinated G-protein and β-arrestin output) partitioned between these arms (PMID:29068002). Within accumbal D2R-MSNs, DRD2 directs aversive learning through an A2aR–PKA–Rap1–MEK cascade (PMID:33301817), and it is required for hippocampal CA3–CA1 LTP and spatial/associative memory (PMID:33264389). DRD2 forms direct or biophysically defined complexes with NR2B, where it disrupts CaMKII–NR2B coupling and suppresses NMDA currents (PMID:17145509), with TAAR1, A2AR, sigma1R, and GHSR, each reconfiguring D2R ligand affinity, G-protein conformation, and β-arrestin recruitment (PMID:26372541, PMID:29632174, PMID:22924752, PMID:29383683, PMID:28300546). Receptor abundance is set post-translationally: the CUL3–KBTBD6/7 E3 ligase ubiquitinates DRD2 at K221/226/241/251/258 to drive proteasomal degradation following internalization (PMID:32572597). Beyond canonical neuronal signaling, astrocytic DRD2 promotes CNS inflammation via a 6-pyruvoyl-tetrahydropterin synthase–PKC-δ–NF-κB axis (PMID:35877595), DRD2 is expressed in olfactory sensory neuron cilia where nasal dopamine tunes olfactory sensitivity (PMID:35263227), and a nuclear pool of DRD2 competes with HIF1α for VHL binding to stabilize HIF1α and promote stress-driven EMT (PMID:34321238). DRD2 is also transcriptionally repressed by REST in glioblastoma stem cells, placing it downstream of REST in tumor invasion control (PMID:30953587).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1998 Medium

    Established that a natural DRD2 coding variant can be signaling-deficient yet not genetically linked to addiction or schizophrenia, separating molecular function from disease association.

    Evidence In vitro signal transduction assay of the Ser311Cys variant plus a large association/sib-pair linkage study

    PMID:9650635

    Open questions at the time
    • Single population studied
    • Does not address contribution of common regulatory variants
  2. 2006 High

    Showed DRD2 directly engages NMDA receptor NR2B subunits at the postsynaptic density, providing a physical basis for dopaminergic modulation of glutamatergic transmission.

    Evidence Reciprocal Co-IP, in vivo biochemistry, and electrophysiology in neostriatum

    PMID:17145509

    Open questions at the time
    • Structural interface not defined
    • Whether interaction is constitutive or strictly agonist-driven in baseline conditions
  3. 2010 Medium

    Demonstrated that cocaine induces D2R-mediated conformational changes in A2AR-D2R and D2R homodimers and raises dopamine affinity, while showing it does not alter cAMP inhibition or GIRK gating, refining which signaling outputs the conformational shift reaches.

    Evidence BRET, radioligand binding, GTPγS assays, and GIRK electrophysiology in heterologous cells

    PMID:20307491

    Open questions at the time
    • Physiological relevance of the conformational change unclear given absent cAMP/GIRK effect
    • Heterologous expression system
  4. 2012 High

    Mapped the D2R ICL3 arginine residues (217-222, 267-269) required for allosteric receptor-receptor signaling within the A2AR/D2R oligomer, defining the structural determinant of heteromer crosstalk.

    Evidence FRET with site-directed mutagenesis and radioligand binding

    PMID:22924752

    Open questions at the time
    • Does not resolve full heteromer architecture
    • In vitro/heterologous context
  5. 2015 High

    Established that TAAR1-D2R heteromerization reciprocally reshapes signaling, biasing D2R away from β-arrestin2 and reducing GSK3β activation, linking the complex to a defined downstream effector.

    Evidence Co-IP, β-arrestin2 complementation, radioligand binding, cAMP assays, and TAAR1 genetic rat models

    PMID:26372541

    Open questions at the time
    • Stoichiometry of the heteromer not defined
    • In vivo behavioral consequences not directly tested here
  6. 2016 Medium

    Identified a DRD2-ROCK-cofilin axis controlling cytoskeletal dynamics and invasion in pituitary tumor cells, extending DRD2 signaling to non-canonical cytoskeletal effectors.

    Evidence Migration/invasion assays, phospho-cofilin western blot, ROCK inhibitor pharmacology, and tumor IHC

    PMID:27519461

    Open questions at the time
    • G-protein vs arrestin dependence not dissected
    • Single tumor type
  7. 2017 High

    Dissected DRD2 G-protein versus β-arrestin contributions to behavior in vivo, showing distinct behaviors map onto different signaling arms and antipsychotic action onto G-protein blockade.

    Evidence Cell-type-specific biased D2R variants expressed in iMSNs of D2R-null mice with behavioral and metabolic readouts

    PMID:29068002

    Open questions at the time
    • Molecular effectors downstream of each arm not fully resolved
    • Restricted to iMSN populations
  8. 2018 High

    Resolved the GHSR-D2R complex as a tetramer recruiting two G-protein trimers and demonstrated heteromerization directly alters Gαi active conformation and nucleotide kinetics, giving a biophysical mechanism for heteromer-driven signal modulation.

    Evidence Purified receptor reconstitution in lipid, GTP binding, and G protein conformational analysis

    PMID:29632174

    Open questions at the time
    • In vivo relevance of the tetramer not established
    • Other heteromer stoichiometries untested
  9. 2018 Medium

    Linked D2R hyperactivity to DISC1 complex formation and Akt-GSK3β dysregulation causing neurite lesions, connecting receptor over-activation to a psychiatric-relevant scaffold and differential antipsychotic protection.

    Evidence FRET for D2R-DISC1, phospho-Akt/GSK3β western blot, DISC1 mutant mice, and pharmacology

    PMID:30597182

    Open questions at the time
    • Directness of D2R-DISC1 binding beyond FRET not confirmed
    • Mechanism coupling complex to GSK3β unresolved
  10. 2018 Medium

    Demonstrated cocaine selectively increases A2AR-D2R and D2R-sigma1R complexes in the accumbens shell and that disrupting A2AR-D2R abolishes A2AR control of cocaine intake, establishing functional necessity of the heteromer in vivo.

    Evidence PLA, BRET, and in vivo TM5 peptide disruption with self-administration behavior

    PMID:28300546 PMID:29383683

    Open questions at the time
    • Single lab across two papers
    • Molecular mechanism of sigma1R complex not detailed
  11. 2019 High

    Placed DRD2 downstream of the transcriptional repressor REST in glioblastoma stem cells, defining a REST-DRD2 axis governing invasion and apoptosis.

    Evidence ChIP-seq, transcriptomics, double knockdown epistasis, and intracranial tumor models

    PMID:30953587

    Open questions at the time
    • Receptor signaling output driving the phenotype not defined
    • Ligand dependence unclear
  12. 2019 Medium

    Used genetic epistasis to show DRD2 is required for full D1R-mediated locomotor responses and psychostimulant sensitization, defining D2R-D1R pathway interaction.

    Evidence D2R knockout mice with behavioral sensitization, dynorphin/c-Fos expression, and D1R agonist challenge

    PMID:31833146

    Open questions at the time
    • Circuit locus of D1R-D2R interaction not pinpointed
    • Cell-autonomous vs network effect unresolved
  13. 2019 Medium

    Established by negative result that DRD3, not DRD2, drives MTORC1-dependent autophagy, delimiting DRD2's signaling repertoire.

    Evidence DRD2-overexpressing cells, drd2 and drd3 KO mice, and MTOR/autophagy analysis

    PMID:31538542

    Open questions at the time
    • Does not exclude DRD2 autophagy roles in other contexts
  14. 2020 High

    Identified KBTBD6/7 as the CUL3 substrate adaptor that ubiquitinates DRD2 at five mapped lysines to drive proteasomal degradation after internalization, defining the post-translational control of receptor abundance.

    Evidence Yeast two-hybrid, Co-IP, site-specific ubiquitination assays, and KBTBD7 knockout mice

    PMID:32572597

    Open questions at the time
    • Deubiquitinase counterpart unknown
    • Tissue-specific regulation of the ligase not mapped
  15. 2020 High

    Defined an A2aR-PKA-Rap1-MEK cascade in accumbal D2R-MSNs that is necessary and sufficient for aversive learning, linking DRD2 to a specific intracellular signaling module for valence.

    Evidence Cell-type-specific AAV pathway manipulation, phosphorylation assays, optogenetics, and aversion behavior

    PMID:33301817

    Open questions at the time
    • How D2R/A2aR balance gates Rap1gap phosphorylation not fully resolved
  16. 2020 High

    Connected iMSN DRD2 to PPARγ-dependent circadian gene reprogramming after cocaine, with PPARγ agonism rescuing the knockout phenotype.

    Evidence Conditional iMSN D2R knockout, RNA-seq, and PPARγ agonist rescue

    PMID:32895370

    Open questions at the time
    • Mechanistic link between D2R signaling and PPARγ not defined
  17. 2021 High

    Demonstrated DRD2 is required for hippocampal CA3-CA1 LTP and multiple forms of memory, establishing a cell-physiological role in synaptic plasticity.

    Evidence D2R KO and intrahippocampal siRNA knockdown with behavioral tasks and in vivo LTP

    PMID:33264389

    Open questions at the time
    • Signaling pathway coupling D2R to LTP not defined
    • Pre- vs postsynaptic locus unresolved
  18. 2021 Medium

    Identified a nuclear DRD2-VHL interaction that competes with HIF1α, stabilizing HIF1α and promoting stress-driven EMT, revealing a non-canonical, ligand-independent nuclear function.

    Evidence Co-IP, stress tumor mouse model, trifluoperazine interface inhibition, and HIF1α ubiquitination assays

    PMID:34321238

    Open questions at the time
    • How a GPCR localizes to the nucleus not explained
    • Direct vs indirect VHL binding not fully resolved
  19. 2021 Medium

    Showed DRD2 interacts with β-arrestin2, DDX5, and eEF1A2 to restrict NF-κB and promote M1 polarization and GSDME pyroptosis in breast cancer, extending DRD2 to immune/cell-death control.

    Evidence Co-IP, antibody array, mass spectrometry, and tumor model

    PMID:33859743

    Open questions at the time
    • DDX5/eEF1A2 interactions lack reciprocal validation
    • Directness of interactions unconfirmed
  20. 2022 High

    Established astrocytic DRD2 as a driver of CNS inflammation via a 6-PTS-PKC-δ-NF-κB axis, distinct from neuronal DRD2 function.

    Evidence Astrocyte-specific conditional knockout, EAE model, pathway analysis, and pharmacological blockade in neuronal-KO background

    PMID:35877595

    Open questions at the time
    • G-protein vs arrestin dependence of the astrocytic effect not dissected
  21. 2022 Medium

    Localized DRD2 to olfactory sensory neuron cilia and showed nasal dopamine-DRD2 signaling tunes olfactory sensitivity with feeding state, extending DRD2 function to peripheral sensory modulation.

    Evidence Immunofluorescence with genetic and pharmacological olfactory assays

    PMID:35263227

    Open questions at the time
    • Downstream OSN signaling pathway not defined
  22. 2022 Medium

    Showed HERV-W ENV directly interacts with D2R, activates PP2A/AKT1/GSK3 signaling, and enhances sodium influx, identifying a viral protein modulator of DRD2.

    Evidence Co-IP, confocal co-localization, and whole-cell patch-clamp

    PMID:35062349

    Open questions at the time
    • Physiological/disease relevance unclear
    • Binding interface unmapped
  23. 2023 High

    Demonstrated cross-species requirement for Drd2 in social behavior, with autoreceptor activation suppressing sociability.

    Evidence Drosophila mutants, dopaminergic-specific conditional KO mice, and agonist/antagonist pharmacology

    PMID:38114631

    Open questions at the time
    • Circuit/effector mechanism for social suppression not defined
  24. 2023 Medium

    Showed hippocampal DRD2 activation rescues sleep-restriction cognitive and plasticity deficits via a Drd2/Cryab/NF-κB anti-neuroinflammatory pathway in microglia.

    Evidence Chronic sleep restriction model, hippocampal agonist delivery, and in vitro microglial assays

    PMID:37543530

    Open questions at the time
    • Direct vs indirect microglial DRD2 action unclear
    • Link between Cryab and NF-κB not mechanistically detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DRD2 partitions among its many heteroreceptor complexes, biased signaling arms, and non-canonical nuclear/transcriptional roles within specific cell types and physiological states remains unresolved.
  • No unified structural model linking heteromer composition to signaling outcome
  • Mechanism of nuclear DRD2 import and ligand-independence undefined
  • In vivo relevance of many heteromers and tumor functions untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 2 GO:0005929 cilium 2 GO:0005634 nucleus 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2 R-HSA-392499 Metabolism of proteins 1
Partners
ADORA2AARRB2GHSRGRIN2BKBTBD7SIGMAR1TAAR1VHL
Complex memberships
A2AR-D2R heteromerD2R-NR2B complexGHSR-D2R tetramerTAAR1-D2R heteromer

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Dopamine stimulation by cocaine enhances heteroreceptor complex formation between D2R and NMDA receptor NR2B subunits in the neostriatum in vivo. The D2R-NR2B interaction is direct and occurs in the postsynaptic density microdomain of excitatory synapses. The enhanced D2R-NR2B interaction disrupts CaMKII association with NR2B, reduces NR2B phosphorylation at Ser1303, and inhibits NMDA receptor-mediated currents in medium-sized striatal neurons. Co-immunoprecipitation, in vivo biochemistry, electrophysiology, behavioral assays Neuron High 17145509
2015 TAAR1 and D2R form heteromeric complexes in heterologous cells and brain tissue. Interaction of TAAR1 with D2R alters subcellular localization of TAAR1, increases D2R agonist binding affinity, reduces β-arrestin2 recruitment to D2R, reduces cAMP signaling of TAAR1 while enhancing its β-arrestin2 signaling, and results in reduced GSK3β activation. Co-immunoprecipitation, β-arrestin2 complementation assays, radioligand binding, cAMP assays, TAAR1 knockout and overexpressing rat models European neuropsychopharmacology High 26372541
2018 Purified GHSR and D2R assemble in a lipid environment as a tetrameric complex (two of each receptor), which further recruits only two G protein trimers per tetramer. Receptor heteromerization directly impacts dopamine-mediated Gi protein activation by inducing a different active conformation of Gαi, linked to higher GTP binding rate and faster dissociation from the heteromeric receptor. Purified receptor reconstitution in lipid environment, GTP binding assays, G protein conformational analysis PNAS High 29632174
2012 The intracellular loop 3 (ICL3) of D2R, specifically arginine residues at positions 217-222 and 267-269, is required for allosteric receptor-receptor interaction within the A2AR/D2R oligomer. Mutation of these residues abolishes the negative allosteric effect of D2R agonist quinpirole on A2AR ligand binding and activation. FRET-based approach, site-directed mutagenesis of D2R ICL3 arginine residues, radioligand binding Journal of neurochemistry High 22924752
2020 KBTBD6/7, a substrate adaptor for CUL3-RING ubiquitin ligase complex, directly interacts with and ubiquitinates D2R at five specific lysine residues (K221, K226, K241, K251, K258), targeting it for proteasome-mediated degradation. Cabergoline-induced D2R internalization leads to cytoplasmic D2R degradation via KBTBD6/7-mediated ubiquitination. KBTBD7 knockout mice show elevated D2R protein levels in pituitary, thalamus, and heart. Yeast two-hybrid, Co-IP, ubiquitination assay with site-specific mutagenesis, CRISPR-Cas9 knockout mice, western blot Acta neuropathologica High 32572597
2017 D2R signals through both G-protein (Gαi/o) and β-arrestin-dependent pathways in indirect pathway medium spiny neurons (iMSNs). Haloperidol antagonism on D2R metabolic signaling is largely mediated by acute blockade of D2R/G-protein signaling. D2R-driven nestlet shredding behavior is similarly driven by D2R/G-protein signaling. D2R-driven locomotion and rearing require coordinated D2R/G-protein and D2R/β-arrestin signaling. Phencyclidine selectively potentiates locomotion via D2R/β-arrestin signaling. Cell type-specific viral expression of biased D2R variants in iMSNs of D2R-null mice, behavioral assays, metabolic signaling readouts Neuropsychopharmacology High 29068002
2021 D2R interacts with β-arrestin2, DDX5, and eEF1A2, and restricts NF-κB signaling pathway activation through these interactions. D2R also facilitates M1 macrophage polarization and triggers GSDME-executed pyroptosis in breast cancer cells. Co-IP, antibody array, mass spectrometry, western blot, cell biology assays, subcutaneous tumor model Theranostics Medium 33859743
2018 Cocaine self-administration specifically increases A2AR-D2R and D2R-sigma1R heteroreceptor complexes in the nucleus accumbens shell. Disruption of A2AR-D2R heteroreceptor complex by A2AR TM5 peptide microinjected into nucleus accumbens completely counteracts the inhibitory effects of A2AR agonist on cocaine self-administration, demonstrating the functional importance of this complex. Proximity ligation assay (PLA), BRET, biochemical binding, microinjection of synthetic peptide, behavioral assays Molecular neurobiology / Pharmacology, biochemistry, and behavior Medium 28300546 29383683
2021 Loss of D2R in knockout mice (Drd2-/-) and intrahippocampal siRNA knockdown impairs spatial memory, associative learning, classical conditioning of eyelid responses, and reduces activity-dependent synaptic plasticity (LTP) at the hippocampal CA3-CA1 synapse, demonstrating D2R is required for hippocampal-dependent memory and plasticity. D2R knockout mice, intrahippocampal Drd2-siRNA injection, behavioral tasks (Morris water maze, trace eyeblink conditioning), in vivo LTP recording Cerebral cortex High 33264389
2020 Cocaine-induced circadian gene reprogramming in the striatum involves dopamine D2R activation in striatal medium spiny neurons (iMSN-D2R). Cell-specific ablation of D2R in iMSNs (iMSN-D2RKO) alters PPARγ-dependent circadian gene expression, and PPARγ agonist administration rescues cocaine-dependent circadian gene control in iMSN-D2RKO mice. Conditional cell-specific D2R knockout, RNA-seq, PPARγ agonist pharmacology, circadian gene expression analysis Nature communications High 32895370
2016 DRD2 agonist reduces migration and invasion of non-functioning pituitary tumor cells. This effect is mediated through ROCK-dependent phosphorylation and inactivation of cofilin (Ser3 phosphorylation). ROCK inhibition abolishes DRD2 agonist-mediated anti-invasive effects. Lower phospho-cofilin levels correlate with invasive tumor behavior. Migration/invasion assays, western blot for phospho-cofilin, ROCK inhibitor pharmacology, cofilin overexpression constructs, IHC on tumor samples Cancer letters Medium 27519461
2019 REST directly represses transcription of the DRD2 gene in glioblastoma stem cells. REST-DRD2 axis regulates invasion and apoptosis in glioblastoma stem cells, confirmed by double knockdown experiments showing DRD2 acts downstream of REST. ChIP-seq (genome-wide DNA binding), transcriptome analysis, gene knockdown (REST and REST+DRD2 double knockdown), mouse intracranial tumor models Neuro-oncology High 30953587
2022 HERV-W ENV directly interacts with D2R (Co-IP and co-localization by laser confocal microscopy) and triggers the PP2A/AKT1/GSK3 signaling pathway via D2R. HERV-W ENV also enhances sodium influx through D2R as shown by whole-cell patch-clamp. Co-IP, laser confocal microscopy, whole-cell patch-clamp, PP2A/AKT1/GSK3 pathway analysis Viruses Medium 35062349
2021 D2R interacts with VHL (von Hippel-Lindau protein) in the nucleus. DRD2 competes with HIF1α for VHL binding, resulting in reduced ubiquitination-mediated degradation of HIF1α and enhanced epithelial-mesenchymal transition of tumor cells under psychological stress conditions. TFP acts as an interface inhibitor between DRD2 and VHL to promote HIF1α degradation. Co-IP, stress-stimulated tumor-bearing mouse model, pharmacological inhibition with trifluoperazine, HIF1α ubiquitination assays, EMT assays Cancer research Medium 34321238
2019 DRD3, but not DRD2, activates autophagy through MTORC1 inhibition in a DRD3-dependent but DRD2-independent mechanism. In drd2 KO mice treated with the DRD2-DRD3 agonist pramipexole, autophagy induction still occurs, confirming DRD2 is not required for this pathway. DRD2-overexpressing cells, drd2 KO mice, drd3 KO mice, MTOR pathway analysis, autophagy markers Autophagy Medium 31538542
2018 D2R over-activation causes neurite lesions in cortical neurons associated with decreased Akt and GSK3β phosphorylation. D2R hyperactivity leads to increased D2R-DISC1 complex formation (demonstrated by FRET), which alters pGSK3β signaling. Aripiprazole prevents D2R-DISC1 complex formation and neurite lesions more effectively than haloperidol, and prevents downregulation of pAkt-pGSK3β. FRET to detect D2R-DISC1 interaction, western blot for Akt/GSK3β phosphorylation, CaMKII immunofluorescence, DISC1 mutant mice, pharmacological treatments Progress in neuro-psychopharmacology & biological psychiatry Medium 30597182
2019 D2R deletion (D2-/- knockout) impairs cocaine- and amphetamine-induced behavioral sensitization. D2R elimination attenuates dynorphin expression (a D1R-regulated direct pathway marker) in naïve and psychostimulant-treated mice. D2R inactivation blunts locomotor and striatal c-Fos responses to D1R agonist SKF81297, indicating D2R is required for full D1R-mediated locomotor responses. D2R knockout mice, behavioral sensitization assays, gene expression analysis (dynorphin, c-Fos), D1R agonist challenge Addiction biology Medium 31833146
2022 DRD2 is expressed in primary cilia and somata of mature olfactory sensory neurons (OSNs). Nasal dopamine is released from sympathetic nerve terminals innervating olfactory mucosa. DA-DRD2 signaling in the nose regulates olfactory function. Local DA synthesis in olfactory mucosa is reduced during hunger, contributing to starvation-induced olfactory enhancement. Immunofluorescence, genetic (DRD2 knockout) and pharmacological approaches, in vivo olfactory behavioral assays PNAS Medium 35263227
2022 Astrocytic DRD2 is upregulated in reactive astrocytes in MS brain. Mice deficient in astrocytic Drd2 show suppression of reactive astrocytes and amelioration of experimental autoimmune encephalomyelitis (EAE). Mechanistically, DRD2 regulates expression of 6-pyruvoyl-tetrahydropterin synthase, which modulates NF-κB activity through protein kinase C-δ. Pharmacological blockade of astrocytic DRD2 inhibits inflammatory response in mice lacking neuronal Drd2. Astrocyte-specific Drd2 conditional knockout, EAE model, NF-κB pathway analysis, PKC-δ assays, pharmacological blockade with DRD2 antagonist Journal of experimental medicine High 35877595
2010 Cocaine produces D2R-mediated conformational changes in A2AR-D2R heterodimers and D2R homodimers (detected by BRET reduction). Cocaine increases DA affinity for hD2LR and produces a small but significant increase in DA-stimulated GTPγS binding. However, cocaine failed to modulate D2R agonist-induced inhibition of cAMP or gating of GIRK channels. BRET in transfected HEK-293T cells, radioligand binding in CHO cells stably expressing hD2LR, GTPγS binding assay, electrophysiology (GIRK channel gating in oocytes) Biochemical and biophysical research communications Medium 20307491
2011 D2R is localized to primary cilia of lactotrophs and melanotrophs in the mouse pituitary gland. Immunoreactivity in primary cilia of lactotrophs changes during the estrous cycle and with genital conditions, while immunolabeling in melanotroph cilia is consistent, suggesting D2R-expressing primary cilia may serve sensory functions for dopamine. Immunohistochemistry with validated antibodies in mouse adenohypophysis Biomedical research Low 21673453
2023 Drd2 gene is required for social functioning across evolutionary distant species (Drosophila and mice). In mice, D2R autoreceptor deletion (in dopaminergic cells) increases sociability but reduces activity. D2R agonist sumanirole decreases sociability in wild-type mice, while antagonist shows no effect, demonstrating activation of D2R autoreceptor suppresses social behavior. Drosophila Drd2 homologue mutants, conditional transgenic mice with dopaminergic-specific or serotonergic-specific Drd2 deletion, D2R agonist/antagonist pharmacology, computational ethological analysis in semi-natural environments Molecular psychiatry High 38114631
1998 The DRD2 Ser311Cys structural variant largely prevents signal transduction following receptor activation (functionally deficient variant). However, in a large association and sib-pair linkage analysis in an American Indian population, this variant was not associated with alcoholism, substance use disorders, or schizophrenia despite its strong functional impairment. In vitro signal transduction assay for Ser311Cys variant, large association and sib-pair linkage analysis (N=459, including 373 sib-pairs) Alcohol Medium 9650635
2023 Activation of hippocampal DRD2 with agonist quinpirole rescues cognitive impairment, synaptic plasticity deficits (synaptophysin, PSD95 downregulation, reduced spine density), and neuroinflammation (NF-κB translocation) in chronic sleep restriction mice. DRD2 regulates Cryab expression, and Drd2/Cryab/NF-κB pathway mediates its anti-neuroinflammatory effect in microglia. Chronic sleep restriction mouse model, hippocampal DRD2 agonist delivery, western blot, behavioral cognition tests, in vitro microglial assays Molecular neurobiology Medium 37543530
2020 D2R-MSNs in the nucleus accumbens regulate aversive behaviors through the A2aR-PKA-Rap1-MEK signaling pathway. Electric foot shock increases phosphorylation of Rap1gap S563 specifically in accumbal D2R-MSNs. AAV-mediated inhibition of PKA, Rap1, or MEK1 in accumbal D2R-MSNs impairs aversive memory; activation potentiates it. Optogenetic inactivation of mesolimbic DAergic neurons induces place aversion attenuated by PKA-Rap1 inhibition in D2R-MSNs. Cell-type-specific AAV-mediated pathway inhibition/activation in D2R-MSNs, phosphorylation assays, passive avoidance tests, optogenetics, real-time place aversion Neurochemistry international High 33301817

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 No association between an allele at the D2 dopamine receptor gene (DRD2) and alcoholism. JAMA 221 1832467
2006 Modulation of D2R-NR2B interactions in response to cocaine. Neuron 198 17145509
2021 Tumor suppressor DRD2 facilitates M1 macrophages and restricts NF-κB signaling to trigger pyroptosis in breast cancer. Theranostics 144 33859743
2008 D2R DNA transfer into the nucleus accumbens attenuates cocaine self-administration in rats. Synapse (New York, N.Y.) 114 18418874
2016 Expression of DRD2 Is Increased in Human Pancreatic Ductal Adenocarcinoma and Inhibitors Slow Tumor Growth in Mice. Gastroenterology 105 27578530
2000 The DRD2 gene in psychiatric and neurological disorders and its phenotypes. Pharmacogenomics 104 11256581
2015 Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 100 26372541
2005 Dopamine D2R DNA transfer in dopamine D2 receptor-deficient mice: effects on ethanol drinking. Life sciences 88 15862598
2011 Dopamine D2 receptor overexpression alters behavior and physiology in Drd2-EGFP mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 83 21209197
2018 Exercise Reduces Dopamine D1R and Increases D2R in Rats: Implications for Addiction. Medicine and science in sports and exercise 77 29613999
2019 Emergence of stable striatal D1R and D2R neuronal ensembles with distinct firing sequence during motor learning. Proceedings of the National Academy of Sciences of the United States of America 71 31072930
2015 An Obesity-Predisposing Variant of the FTO Gene Regulates D2R-Dependent Reward Learning. The Journal of neuroscience : the official journal of the Society for Neuroscience 69 26354923
2021 Extracellular Matrix in Synthetic Hydrogel-Based Prostate Cancer Organoids Regulate Therapeutic Response to EZH2 and DRD2 Inhibitors. Advanced materials (Deerfield Beach, Fla.) 64 34676924
2012 Dopamine genes (DRD2/ANKK1-TaqA1 and DRD4-7R) and executive function: their interaction with obesity. PloS one 61 22848508
2013 The dopamine receptor D2 (DRD2) SNP rs1076560 is associated with opioid addiction. Annals of human genetics 59 24359476
2017 Validation of dopamine receptor DRD1 and DRD2 antibodies using receptor deficient mice. Amino acids 55 28316027
2012 DRD2 polymorphisms modulate reward and emotion processing, dopamine neurotransmission and openness to experience. Cortex; a journal devoted to the study of the nervous system and behavior 54 22424959
2018 GHSR-D2R heteromerization modulates dopamine signaling through an effect on G protein conformation. Proceedings of the National Academy of Sciences of the United States of America 53 29632174
2017 DRD2 co-expression network and a related polygenic index predict imaging, behavioral and clinical phenotypes linked to schizophrenia. Translational psychiatry 52 28094815
2017 Dopamine receptor type 2 (DRD2) and somatostatin receptor type 2 (SSTR2) agonists are effective in inhibiting proliferation of progenitor/stem-like cells isolated from nonfunctioning pituitary tumors. International journal of cancer 51 28120505
2014 Cannabinoid, melanocortin and opioid receptor expression on DRD1 and DRD2 subpopulations in rat striatum. Frontiers in neuroanatomy 49 24723856
2006 Association between the DRD2 A1 allele and response to methadone and buprenorphine maintenance treatments. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 46 16583408
2018 Disruption of A2AR-D2R Heteroreceptor Complexes After A2AR Transmembrane 5 Peptide Administration Enhances Cocaine Self-Administration in Rats. Molecular neurobiology 45 29383683
2017 Cocaine self-administration specifically increases A2AR-D2R and D2R-sigma1R heteroreceptor complexes in the rat nucleus accumbens shell. Relevance for cocaine use disorder. Pharmacology, biochemistry, and behavior 42 28300546
2018 A2AR-D2R Heteroreceptor Complexes in Cocaine Reward and Addiction. Trends in pharmacological sciences 41 30384981
2012 Molecular determinants of A2AR-D2R allosterism: role of the intracellular loop 3 of the D2R. Journal of neurochemistry 41 22924752
2009 Association between dopaminergic genes (SLC6A3 and DRD2) and stuttering among Han Chinese. Journal of human genetics 41 19590515
2017 DRD2: Bridging the Genome and Ingestive Behavior. Trends in cognitive sciences 39 28372879
2015 Common variants in DRD2 are associated with sleep duration: the CARe consortium. Human molecular genetics 39 26464489
2014 Association between DRD2 (rs1799732 and rs1801028) and ANKK1 (rs1800497) polymorphisms and schizophrenia: a meta-analysis. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 39 25504812
2005 Polymorphisms of the dopamine receptor gene DRD2 and colorectal cancer risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 39 16030094
2005 Sequence analysis of Drd2, Drd4, and Dat1 in SHR and WKY rat strains. Behavioral and brain functions : BBF 39 16356184
2016 Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status. Synapse (New York, N.Y.) 37 27241797
2010 Association of DRD2 gene polymorphisms with mood disorders: a meta-analysis. Journal of affective disorders 36 21130502
2006 Polymorphism of DRD2 gene and ADHD. Neuro endocrinology letters 35 16648784
1998 A functionally deficient DRD2 variant [Ser311Cys] is not linked to alcoholism and substance abuse. Alcohol (Fayetteville, N.Y.) 35 9650635
2011 Stress-induced depressive behaviors are correlated with Par-4 and DRD2 expression in rat striatum. Behavioural brain research 34 21596067
2012 Identification of a novel ANKK1 and other dopaminergic (DRD2 and DBH) gene variants in migraine susceptibility. Neuromolecular medicine 31 22875483
2021 Dopamine D2R is Required for Hippocampal-dependent Memory and Plasticity at the CA3-CA1 Synapse. Cerebral cortex (New York, N.Y. : 1991) 30 33264389
2014 The DRD2 rs1800497 polymorphism increase the risk of mood disorder: evidence from an update meta-analysis. Journal of affective disorders 30 24655768
2001 Dopamine D2 receptor gene (DRD2) is associated with alcoholism with conduct disorder. Alcoholism, clinical and experimental research 30 11236830
2000 Reappraisal of the association between the DRD2 gene, alcoholism and addiction. European psychiatry : the journal of the Association of European Psychiatrists 30 10881204
2023 Activation of the Hippocampal DRD2 Alleviates Neuroinflammation, Synaptic Plasticity Damage and Cognitive Impairment After Sleep Deprivation. Molecular neurobiology 29 37543530
2021 Optogenetic activation of striatal D1R and D2R cells differentially engages downstream connected areas beyond the basal ganglia. Cell reports 29 34965430
2020 The KBTBD6/7-DRD2 axis regulates pituitary adenoma sensitivity to dopamine agonist treatment. Acta neuropathologica 29 32572597
2016 Variants in the DRD2 locus and antipsychotic-related prolactin levels: A meta-analysis. Psychoneuroendocrinology 29 27333159
2008 The interaction of DRD2 and violent victimization on depression: an analysis by gender and race. Journal of affective disorders 29 18501970
2022 HERV-W Envelope Triggers Abnormal Dopaminergic Neuron Process through DRD2/PP2A/AKT1/GSK3 for Schizophrenia Risk. Viruses 28 35062349
2019 DRD3 (dopamine receptor D3) but not DRD2 activates autophagy through MTORC1 inhibition preserving protein synthesis. Autophagy 28 31538542
2006 The DRD2 TaqI-B polymorphism and its relationship to smoking abstinence and withdrawal symptoms. The pharmacogenomics journal 28 17189962
2020 Cocaine-mediated circadian reprogramming in the striatum through dopamine D2R and PPARγ activation. Nature communications 27 32895370
2016 Dopamine receptor type 2 (DRD2) inhibits migration and invasion of human tumorous pituitary cells through ROCK-mediated cofilin inactivation. Cancer letters 27 27519461
2019 REST-DRD2 mechanism impacts glioblastoma stem cell-mediated tumorigenesis. Neuro-oncology 26 30953587
2017 Engineered D2R Variants Reveal the Balanced and Biased Contributions of G-Protein and β-Arrestin to Dopamine-Dependent Functions. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 26 29068002
2012 Early postnatal experience and DRD2 genotype affect dopamine receptor expression in the rat ventral striatum. Behavioural brain research 26 23036844
2010 Genetic polymorphisms in the DRD2, DRD3, and SLC6A3 gene in elderly patients with delirium. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 26 19309018
2019 Synergistic effects between ADORA2A and DRD2 genes on anxiety disorders in children with ADHD. Progress in neuro-psychopharmacology & biological psychiatry 25 30946941
2018 Functionally Biased D2R Antagonists: Targeting the β-Arrestin Pathway to Improve Antipsychotic Treatment. ACS chemical biology 25 29485852
2017 Impact of DRD2/ANKK1 and COMT Polymorphisms on Attention and Cognitive Functions in Schizophrenia. PloS one 25 28085950
2014 Polymorphisms of DRD2 and DRD3 genes and Parkinson's disease: A meta-analysis. Biomedical reports 25 24649110
2008 Drd2 expression in the high alcohol-preferring and low alcohol-preferring mice. Mammalian genome : official journal of the International Mammalian Genome Society 25 18214604
2014 Association of COMT and COMT-DRD2 interaction with creative potential. Frontiers in human neuroscience 24 24782743
2014 The relationship between DRD2 gene polymorphisms (C957T and C939T) and schizophrenia: a meta-analysis. Neuroscience letters 24 25240594
2021 Psychologic Stress Drives Progression of Malignant Tumors via DRD2/HIF1α Signaling. Cancer research 23 34321238
2014 DRD2/CHRNA5 interaction on prefrontal biology and physiology during working memory. PloS one 23 24819610
2014 NCAM1-TTC12-ANKK1-DRD2 variants and smoking motives as intermediate phenotypes for nicotine dependence. Psychopharmacology 23 25273375
2013 ANKK1 and DRD2 pharmacogenetics of disulfiram treatment for cocaine abuse. Pharmacogenetics and genomics 23 23635803
2012 Depressive rumination and the C957T polymorphism of the DRD2 gene. Cognitive, affective & behavioral neuroscience 23 22864973
2019 GPR88 in D1R-Type and D2R-Type Medium Spiny Neurons Differentially Regulates Affective and Motor Behavior. eNeuro 22 31346000
2019 NURR1 and ERR1 Modulate the Expression of Genes of a DRD2 Coexpression Network Enriched for Schizophrenia Risk. The Journal of neuroscience : the official journal of the Society for Neuroscience 22 31811028
1996 Dopamine D2 receptor gene (DRD2) haplotypes in Caucasians. Gene 22 8972908
2019 Morphine Differentially Alters the Synaptic and Intrinsic Properties of D1R- and D2R-Expressing Medium Spiny Neurons in the Nucleus Accumbens. Frontiers in synaptic neuroscience 21 31920618
2017 Associations of IGF2 and DRD2 polymorphisms with laying traits in Muscovy duck. PeerJ 21 29181280
2013 Lack of association between DRD2 and OPRM1 genotypes and adiposity. International journal of obesity (2005) 21 23917806
2010 Cocaine produces D2R-mediated conformational changes in the adenosine A(2A)R-dopamine D2R heteromer. Biochemical and biophysical research communications 21 20307491
2021 D1R- and D2R-Medium-Sized Spiny Neurons Diversity: Insights Into Striatal Vulnerability to Huntington's Disease Mutation. Frontiers in cellular neuroscience 20 33642998
2021 Effects of the DRD2/3 antagonist ONC201 and radiation in glioblastoma. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 20 34097975
2020 Fluoride Affects Dopamine Metabolism and Causes Changes in the Expression of Dopamine Receptors (D1R and D2R) in Chosen Brain Structures of Morphine-Dependent Rats. International journal of molecular sciences 20 32235357
2020 Accumbal D2R-medium spiny neurons regulate aversive behaviors through PKA-Rap1 pathway. Neurochemistry international 20 33301817
2023 Psilocin suppresses methamphetamine-induced hyperlocomotion and acquisition of conditioned place preference via D2R-mediated ERK signaling. CNS neuroscience & therapeutics 19 36627756
2022 Olfactory regulation by dopamine and DRD2 receptor in the nose. Proceedings of the National Academy of Sciences of the United States of America 19 35263227
2022 Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis. The Journal of experimental medicine 19 35877595
2009 Hypothalamic orexin, OX1, alphaMSH, NPY and MCRs expression in dopaminergic D2R knockout mice. Neuropeptides 19 19570576
2016 Diversity and bias through dopamine D2R heteroreceptor complexes. Current opinion in pharmacology 18 27838588
2015 Low expression of D2R and Wntless correlates with high motivation for heroin. Behavioral neuroscience 18 26501177
2005 Evolution of the DRD2 gene haplotype and its association with alcoholism in Mexican Americans. Alcohol (Fayetteville, N.Y.) 18 16396745
2023 Dorsal BNST DRD2+ neurons mediate sex-specific anxiety-like behavior induced by chronic social isolation. Cell reports 17 37453056
2013 Gender-specific association of the SLC6A4 and DRD2 gene variants in bipolar disorder. The international journal of neuropsychopharmacology 17 24229495
2019 Unravelling the interaction between the DRD2 and DRD4 genes, personality traits and concussion risk. BMJ open sport & exercise medicine 16 30815277
2019 Behavioral sensitization and cellular responses to psychostimulants are reduced in D2R knockout mice. Addiction biology 16 31833146
2017 Variation on the dopamine D2 receptor gene (DRD2) is associated with basal ganglia-to-frontal structural connectivity. NeuroImage 16 28392487
2016 The mRNA expression of DRD2, PI3KCB, and AKT1 in the blood of acute schizophrenia patients. Psychiatry research 16 27449010
2013 Preincubation of pituitary tumor cells with the epidrugs zebularine and trichostatin A are permissive for retinoic acid-augmented expression of the BMP-4 and D2R genes. Endocrinology 16 23539512
2011 Immunohistochemical demonstration of dopamine receptor D2R in the primary cilia of the mouse pituitary gland. Biomedical research (Tokyo, Japan) 16 21673453
2000 The DRD2 gene and the risk for alcohol dependence in bipolar patients. European psychiatry : the journal of the Association of European Psychiatrists 16 10881206
2023 Ventral Subiculum Inputs to Nucleus Accumbens Medial Shell Preferentially Innervate D2R Medium Spiny Neurons and Contain Calcium Permeable AMPARs. The Journal of neuroscience : the official journal of the Society for Neuroscience 15 36609456
2023 The human neuropsychiatric risk gene Drd2 is necessary for social functioning across evolutionary distant species. Molecular psychiatry 15 38114631
2018 Aripiprazole and haloperidol protect neurite lesions via reducing excessive D2R-DISC1 complex formation. Progress in neuro-psychopharmacology & biological psychiatry 15 30597182
2017 DRD2 and ANKK1 genes associate with late-onset heroin dependence in men. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 15 28854834
2012 Analysis of dopamine D2 receptor (DRD2) gene polymorphisms in cannabinoid addicts. Journal of forensic sciences 15 22536882

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