{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"P14416","secondaryAccessions":["Q9NZR3","Q9UPA9"],"uniProtkbId":"DRD2_HUMAN","entryAudit":{"firstPublicDate":"1990-01-01","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"1990-04-01","entryVersion":254,"sequenceVersion":2},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Dopamine receptor D2"}},"alternativeNames":[{"fullName":{"value":"Dopamine D2 receptor"}}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"15389757"},{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:3023"}],"value":"DRD2"}}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P61168"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P61169"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21645528"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32103023"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32528175"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33353947"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33571431"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37221270"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"39103320"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"40683247"}],"value":"G protein-coupled receptor for dopamine, a catecholamine neurotransmitter hormone that functions as the brain's 'reward chemical', driving motivation, reinforcement learning and pleasure (PubMed:21645528, PubMed:32103023, PubMed:32528175, PubMed:33353947, PubMed:33571431, PubMed:37221270, PubMed:39103320). Dopamine binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase (PubMed:32103023, PubMed:32528175, PubMed:33353947, PubMed:33571431, PubMed:37221270). Dopamine receptors can be classified in two categories: (1) DRD2 (together with DRD3 and DRD4) is a D2-type receptor and is coupled to G(i)/G(o) G proteins, mediating inhibition of adenylate cyclase activity, while D1-type receptors (DRD1 and DRD5) are coupled to G(s) G proteins and promote activation of adenylate cyclase activity (PubMed:32103023, PubMed:32528175, PubMed:33353947, PubMed:33571431, PubMed:37221270). In the central nervous system, DRD2 is mainly coupled to G(o)/GNAO1 (By similarity). D1- and D2-type dopamine receptors have antagonistic effects, particularly in the brain's striatum, where they govern voluntary movement and reward: D1-type receptors generally stimulate neural activity and promotes action, while D2-type receptors tend to inhibit neural activity and suppress movement (By similarity). DRD1 and DRD2 are the most abundant dopamine receptors in the central nervous system, especially in the basal ganglia and the prefrontal cortex (PubMed:33571431). DRD2 receptor plays a key role in risky decision-making by modulating reward sensitivity and executive control; DRD2 activation in nucleus accumbens cells leading to increased risk-taking and impulsivity (By similarity). DRD2 can also couple with G(q) by forming a heteromer with the ghrelin receptor GHSR in neurons independently of ghrelin (By similarity). Following DRD2 activation by dopamine in lumbosacral defecation centers, GHSR acts as a coreceptor promoting DRD2 coupling to G(q) at the expense of G(i)/G(o), regulating defecation (By similarity). In addition to dopamine, also acts as a receptor for tryptophan-derived metabolites in intestinal epithelial cells: activation by tryptophan metabolites produced by the gut microbiota initiates a phospholipase-C-dependent signaling that promotes colonization resistance by pathogens by controlling actin cytoskeletal organization in the gut epithelium (By similarity). Positively regulates postnatal regression of retinal hyaloid vessels via suppression of VEGFR2/KDR activity, downstream of OPN5 (By similarity). Also acts as a receptor for D-lysergic (LSD) psychedelic drug (PubMed:40683247)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32103023"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33353947"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33571431"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"37221270"}],"value":"Activated by small-molecule agonist bromocriptine (PubMed:33571431). Activated by the pan-agonist rotigotine, which activates all five dopamine receptors (PubMed:37221270). Inhibited by antipsychotic drug haloperidol; which acts as an antagonist of DRD2 (PubMed:32103023). Specifically inhibited by antipsychotic drug spiperone; which acts as a specific and potent antagonist of DRD2 (PubMed:33353947)"}],"commentType":"ACTIVITY REGULATION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P61168"},{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P61169"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15857609"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"17550964"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21184734"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21645528"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"39103320"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"40781549"}],"value":"Interacts with GNAO1, GNB1 and GNG2; interaction with a heterotrimeric G protein complex is essential for receptor activity (PubMed:39103320). Interacts with G(i) proteins, GNAI1, GNAI2 and GNAI3 (By similarity). Interacts with GNAI2 isoform sGi2; the interaction allows the creation of an intracellular pool of DRD2 that can be released to cell surface upon agonist stimulation (PubMed:17550964). Forms heteromers with DRD1 (By similarity). Forms heterooligomers with DRD4; the interaction with DRD4 may modulate agonist-induced downstream signaling (PubMed:21184734). Interacts with CADPS and CADPS2 (PubMed:15857609). Interacts with GPRASP1, PPP1R9B and CLIC6 (By similarity). Interacts with ARRB2; leading to receptor desensitization (PubMed:40781549). Interacts with HTR2A (PubMed:21645528). Interacts with KCNA2 (By similarity). Interacts with GHSR; forms a heteromer with GHSR in neurons (By similarity)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"P14416","intActId":"EBI-2928178"},"interactantTwo":{"uniProtKBAccession":"Q9NRI5","geneName":"DISC1","intActId":"EBI-529989"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P14416","intActId":"EBI-2928178"},"interactantTwo":{"uniProtKBAccession":"P14416","geneName":"DRD2","intActId":"EBI-2928178"},"numberOfExperiments":9,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P14416","intActId":"EBI-2928178"},"interactantTwo":{"uniProtKBAccession":"Q01959","geneName":"SLC6A3","intActId":"EBI-6661445"},"numberOfExperiments":4,"organismDiffer":false}]},{"commentType":"SUBCELLULAR LOCATION","note":{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P61169"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23493394"}],"value":"Mainly active on postsynaptic membrane (By similarity). Specifically localizes to special plasma membrane microcompartments (PubMed:23493394)"}]},"subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P61169"}],"value":"Postsynaptic cell membrane","id":"SL-0219"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32528175"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33571431"}],"value":"Multi-pass membrane protein","id":"SL-9909"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"21645528"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23493394"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26535572"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8413587"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32528175"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33571431"}],"value":"Multi-pass membrane protein","id":"SL-9909"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26535572"}],"value":"Golgi apparatus membrane","id":"SL-0134"},"topology":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32528175"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33571431"}],"value":"Multi-pass membrane protein","id":"SL-9909"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"1"},"synonyms":[{"value":"D2(Long)"},{"value":"D2A"}],"isoformIds":["P14416-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"2"},"synonyms":[{"value":"D2(Short)"},{"value":"D2B"}],"isoformIds":["P14416-2"],"sequenceIds":["VSP_001870"],"isoformSequenceStatus":"Described"},{"name":{"value":"3"},"synonyms":[{"value":"D2(Longer)"}],"isoformIds":["P14416-3"],"sequenceIds":["VSP_026455"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2531656"}],"value":"Expressed in the anterior pituitary gland"}],"commentType":"TISSUE SPECIFICITY","molecule":"Isoform 1"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2531656"}],"value":"Expressed in the anterior pituitary gland"}],"commentType":"TISSUE SPECIFICITY","molecule":"Isoform 2"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"26535572"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"7931316"}],"value":"Palmitoylated (PubMed:7931316, PubMed:26535572). Palmitoylation which is required for proper localization to the plasma membrane and stability of the receptor could be carried on by ZDHHC4, ZDHHC3 and ZDHHC8 (PubMed:26535572)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2953072"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33859231"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"40781549"}],"value":"Phosphorylation of intracellular loop 3 by GRK2 and GRK3 following prolonged stimulation by dopamine, promoting association with beta-arrestin (ARRB1 or ARRB2), leading to receptor desensitization and negative regulation of G protein-coupled receptor signaling (PubMed:33859231, PubMed:40781549). Constitutive phosphorylation (in absence of dopamine activation) by some isoforms of PKC-beta (PRKCB) inhibits G protein-coupled receptor signaling (PubMed:2953072)"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15389757"}],"value":"Genetic variations in DRD2 may determine the genetic susceptibility to alcoholism [MIM:103780]. Genetic variations in DRD2 might be a protective factor against the development of withdrawal symptoms but might also be a risk factor in a highly burdened subgroup of alcoholics with a paternal and grandpaternal history of alcoholism and might contribute to suicide risk in alcoholics"}],"commentType":"POLYMORPHISM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000255","source":"PROSITE-ProRule","id":"PRU00521"}],"value":"Belongs to the G protein-coupled receptor 1 family"}],"commentType":"SIMILARITY"}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":443,"modifier":"EXACT"}},"description":"Dopamine receptor D2","featureId":"PRO_0000069387"},{"type":"Topological 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