Dopamine receptor D2

Dopamine receptor D2
Rendering based on PDB 1I15.
Available structures PDB 1I15, 2HLB
Identifiers
Symbols	DRD2; D2DR; D2R
External IDs	OMIM: 126450 MGI: 94924 HomoloGene: 22561 IUPHAR: D2 GeneCards: DRD2 Gene
Gene Ontology Molecular function • dopamine receptor activity, coupled via Gi/Go • dopamine D2 receptor activity • receptor activity • G-protein coupled receptor activity • receptor binding • protein binding • drug binding • potassium channel regulator activity • ionotropic glutamate receptor binding Cellular component • acrosomal vesicle • soluble fraction • plasma membrane • plasma membrane • integral to plasma membrane • integral to plasma membrane • postsynaptic density • lateral plasma membrane • flagellum • endocytic vesicle • axon • dendrite • synaptic vesicle membrane • cytoplasmic vesicle • dendritic spine • perikaryon • axon terminus Biological process • temperature homeostasis • response to hypoxia • synaptic transmission, dopaminergic • response to amphetamine • neurological system process involved in regulation of systemic arterial blood pressure • regulation of heart rate • regulation of sodium ion transport • G-protein coupled receptor internalization • positive regulation of neuroblast proliferation • positive regulation of receptor internalization • cellular calcium ion homeostasis • G-protein signaling, coupled to cAMP nucleotide second messenger • negative regulation of adenylate cyclase activity • negative regulation of adenylate cyclase activity • inhibition of adenylate cyclase activity by dopamine receptor signaling pathway • inhibition of adenylate cyclase activity by dopamine receptor signaling pathway • intracellular protein kinase cascade • neuron-neuron synaptic transmission • axonogenesis • synapse assembly • sensory perception of smell • long-term memory • grooming behavior • locomotory behavior • adult walking behavior • feeding behavior • protein localization • negative regulation of cell proliferation • associative learning • visual learning • response to light stimulus • response to toxin • response to iron ion • regulation of dopamine secretion • Wnt receptor signaling pathway • cerebral cortex GABAergic interneuron migration • adenohypophysis development • negative regulation of cell migration • peristalsis • regulation of cAMP metabolic process • forebrain development • auditory behavior • activation of protein kinase activity • regulation of synaptic transmission, GABAergic • circadian regulation of gene expression • response to histamine • response to nicotine • positive regulation of multicellular organism growth • response to cocaine • negative regulation of circadian sleep/wake cycle, sleep • dopamine metabolic process • response to drug • regulation of potassium ion transport • response to morphine • regulation of MAPKKK cascade • pigmentation • regulation of phosphoprotein phosphatase activity • positive regulation of G-protein coupled receptor protein signaling pathway • negative regulation of blood pressure • positive regulation of transcription from RNA polymerase II promoter • phosphatidylinositol metabolic process • negative regulation of insulin secretion • behavioral response to cocaine • behavioral response to ethanol • regulation of long-term neuronal synaptic plasticity • response to axon injury • branching morphogenesis of a nerve • arachidonic acid secretion • negative regulation of protein secretion • release of sequestered calcium ion into cytosol • reduction of cytosolic calcium ion concentration • elevation of cytosolic calcium ion concentration involved in G-protein signaling coupled to IP3 second messenger • regulation of dopamine uptake • positive regulation of dopamine uptake • negative regulation of protein kinase B signaling cascade • negative regulation of calcium ion transport via voltage-gated calcium channel activity • negative regulation of calcium ion transport via voltage-gated calcium channel activity • negative regulation of synaptic transmission, glutamatergic • positive regulation of growth hormone secretion • prepulse inhibition • activation of phospholipase C activity by dopamine receptor signaling pathway • negative regulation of dopamine receptor signaling pathway • positive regulation of ERK1 and ERK2 cascade Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1813	13489
Ensembl	ENSG00000149295	ENSMUSG00000032259
UniProt	P14416	Q0VGH9
RefSeq (mRNA)	NM_000795.3	NM_010077.2
RefSeq (protein)	NP_000786.1	NP_034207.2
Location (UCSC)	Chr 11: 113.28 – 113.35 Mb	Chr 9: 49.15 – 49.22 Mb
PubMed search	[1]	[2]

Dopamine receptor D₂, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene.

Function

This gene encodes the D₂ subtype of the dopamine receptor. This G protein-coupled receptor inhibits adenylyl cyclase activity. A missense mutation in this gene causes myoclonus dystonia; other mutations have been associated with schizophrenia.^[1]

Alternative splicing of this gene results in two transcript variants encoding different isoforms. A third variant has been described, but it has not been determined whether this form is normal or due to aberrant splicing.^[2]

Genetics

Allelic variants:

• A-241G
• C132T, G423A, T765C, C939T, C957T, and G1101A ^[3]
• Cys311Ser
• -141C insertion/deletion^[4]

The polymorphisms has been investigated with respect to association with schizophrenia.^[5]

Some researchers have previously associated the polymorphism Taq 1A (rs1800497) to the DRD2 gene. However, the polymorphism sits in exon 8 of the ANKK1 gene.^[6]

Ligands

Most of the older antipsychotic drugs such as chlorpromazine and haloperidol are antagonists for the dopamine D₂ receptor, but are, in general, very unselective, at best selective only for the "D₂-like family" receptors and so binding to D₂, D₃ and D₄, and often also to many other receptors such as those for serotonin and histamine, resulting in a range of side-effects and making them poor agents for scientific research. In similar manner, older dopamine agonists used for Parkinson's disease such as bromocriptine and cabergoline are poorly selective for one dopamine receptor over another, and, although most of these agents do act as D₂ agonists, they affect other subtypes as well. Several selective D₂ ligands are, however, now available, and this number is likely to increase as further research progresses.

Agonists

• Aplindore - partial agonist
• Aripiprazole (Abilify in USA) - partial agonist^[7]
• GSK-789,472 - mixed D₂ partial agonist / D₃ antagonist, with good selectivity over other receptors ^[8]
• Talipexole - selective for D₂ over other dopamine receptors, but also acts as α₂-adrenoceptor agonist and 5HT₃ antagonist.
• Piribedil - also D3 receptor agonist and α₂-adrenergic antagonist
• LSD - in vitro, LSD was found to be a partial agonist and potentiates dopamine-mediated prolactin secretion in lactotrophs.^[9] LSD is also a 5HT_2A agonist.
• Pramipexole - also D3, D4 receptor agonist
• Quinpirole - also D3 receptor agonist
• Quinelorane
• Methylphenidate^{[citation needed]}
• Salvinorin A - partial agonist. Also k-opioid agonist.
• Bromocriptine
• Ropinirole

Antagonists

• L-741,626 (3-[4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole) - highly selective D₂ antagonist
• Melperone - D₂ antagonist but also 5HT_2A antagonist
• Risperidone - D₂ antagonist but also 5HT_2A antagonist
• Ziprasidone - D₂ antagonist but also 5HT_2A antagonist
• Raclopride - Radiolabled C¹¹raclopride is commonly employed in Positron emission tomography studies^[10]
• Clozapine
• Quetiapine ^[11]
• Domperidone - D₂ and D₃ antagonist

D₂Sh selective (presynaptic autoreceptors)

• Amisulpride (low doses)
• UH-232

Interactions

Dopamine receptor D2 has been shown to interact with Adenosine A2A receptor,^[12] EPB41L1^[13] and PPP1R9B.^[14]

See also

• Dopamine receptor

References

1. ^ "Gene Overview of All Published Schizophrenia-Association Studies for DRD2". Schizophrenia Research Forum. 2009-03-26. http://www.schizophreniaforum.org/res/sczgene/geneoverview.asp?geneid=93. Retrieved 2009-06-09. 
2. ^ "Entrez Gene: DRD2 dopamine receptor D2". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1813. 
3. ^ http://hmg.oxfordjournals.org/content/12/3/205.short
4. ^ T. Arinami, M. Gao, H. Hamaguchi, M. Toru (1997). "A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia". Human Molecular Genetics 6 (4): 577–582. doi:10.1093/hmg/6.4.577. PMID 9097961. 
5. ^ Glatt SJ, Faraone SV, Tsuang MT (July 2004). "DRD2 -141C insertion/deletion polymorphism is not associated with schizophrenia: results of a meta-analysis". Am. J. Med. Genet. B Neuropsychiatr. Genet. 128B (1): 21–3. doi:10.1002/ajmg.b.30007. PMID 15211624. 
6. ^ M. Lucht, D. Rosskopf (July 2008). "Comment on "Genetically determined differences in learning from errors"". Science 321 (5886): 200. doi:10.1126/science.1155372. PMID 18621654. http://www.sciencemag.org/cgi/content/full/321/5886/200a. 
7. ^ "Clinical Pharmacology for Abilify". RxList.com. 2010-01-21. http://www.rxlist.com/abilify-drug.htm. Retrieved 2010-01-21. 
8. ^ Holmes IP, Blunt RJ, Lorthioir OE, Blowers SM, Gribble A, Payne AH, Stansfield IG, Wood M, Woollard PM, Reavill C, Howes CM, Micheli F, Di Fabio R, Donati D, Terreni S, Hamprecht D, Arista L, Worby A, Watson SP (March 2010). "The identification of a selective dopamine D2 partial agonist, D3 antagonist displaying high levels of brain exposure". Bioorganic & Medicinal Chemistry Letters 20 (6): 2013–6. doi:10.1016/j.bmcl.2010.01.090. PMID 20153647. 
9. ^ Giacomelli S, Palmery M, Romanelli L, Cheng CY, Silvestrini B (1998). "Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro". Life Sci. 63 (3): 215–22. doi:10.1016/S0024-3205(98)00262-8. PMID 9698051. 
10. ^ Wang GJ, Volkow ND, Thanos PK, Fowler JS (2004). "Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review". J Addict Dis 23 (3): 39–53. doi:10.1300/J069v23n03_04. PMID 15256343. 
11. ^ http://ajp.psychiatryonline.org/cgi/content/abstract/156/6/876
12. ^ Kamiya T, Saitoh O, Yoshioka K, Nakata H (June 2003). "Oligomerization of adenosine A2A and dopamine D2 receptors in living cells". Biochem. Biophys. Res. Commun. 306 (2): 544–9. doi:10.1016/S0006-291X(03)00991-4. PMID 12804599. 
13. ^ Binda AV, Kabbani N, Lin R, Levenson R (September 2002). "D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1N". Mol. Pharmacol. 62 (3): 507–13. doi:10.1124/mol.62.3.507. PMID 12181426. 
14. ^ Smith FD, Oxford GS, Milgram SL (July 1999). "Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting protein". J. Biol. Chem. 274 (28): 19894–900. doi:10.1074/jbc.274.28.19894. PMID 10391935. 

Further reading

• Missale C, Nash SR, Robinson SW, et al. (1998). "Dopamine receptors: from structure to function". Physiol. Rev. 78 (1): 189–225. PMID 9457173. 
• Sidhu A, Niznik HB (2000). "Coupling of dopamine receptor subtypes to multiple and diverse G proteins". Int. J. Dev. Neurosci. 18 (7): 669–77. doi:10.1016/S0736-5748(00)00033-2. PMID 10978845. 
• Araki K, Kuwano R, Morii K, et al. (1993). "Structure and expression of human and rat D2 dopamine receptor genes". Neurochem. Int. 21 (1): 91–8. doi:10.1016/0197-0186(92)90071-X. PMID 1363862. 
• Eubanks JH, Djabali M, Selleri L, et al. (1993). "Structure and linkage of the D2 dopamine receptor and neural cell adhesion molecule genes on human chromosome 11q23". Genomics 14 (4): 1010–8. doi:10.1016/S0888-7543(05)80124-7. PMID 1478642. 
• Dearry A, Falardeau P, Shores C, Caron MG (1992). "D2 dopamine receptors in the human retina: cloning of cDNA and localization of mRNA". Cell. Mol. Neurobiol. 11 (5): 437–53. doi:10.1007/BF00734808. PMID 1835903. 
• Sarkar G, Kapelner S, Grandy DK, et al. (1992). "Direct sequencing of the dopamine D2 receptor (DRD2) in schizophrenics reveals three polymorphisms but no structural change in the receptor". Genomics 11 (1): 8–14. doi:10.1016/0888-7543(91)90096-W. PMID 1837284. 
• Stormann TM, Gdula DC, Weiner DM, Brann MR (1990). "Molecular cloning and expression of a dopamine D2 receptor from human retina". Mol. Pharmacol. 37 (1): 1–6. PMID 2137193. 
• Robakis NK, Mohamadi M, Fu DY, et al. (1990). "Human retina D2 receptor cDNAs have multiple polyadenylation sites and differ from a pituitary clone at the 5' non-coding region". Nucleic Acids Res. 18 (5): 1299. doi:10.1093/nar/18.5.1299. PMC 330461. PMID 2138729. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=330461. 
• Selbie LA, Hayes G, Shine J (1990). "DNA homology screening: isolation and characterization of the human D2A dopamine receptor subtype". Adv. Second Messenger Phosphoprotein Res. 24: 9–14. PMID 2144985. 
• Monsma FJ, McVittie LD, Gerfen CR, et al. (1990). "Multiple D2 dopamine receptors produced by alternative RNA splicing". Nature 342 (6252): 926–9. doi:10.1038/342926a0. PMID 2480527. 
• Dal Toso R, Sommer B, Ewert M, et al. (1990). "The dopamine D2 receptor: two molecular forms generated by alternative splicing". EMBO J. 8 (13): 4025–34. PMC 401577. PMID 2531656. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=401577. 
• Grandy DK, Marchionni MA, Makam H, et al. (1990). "Cloning of the cDNA and gene for a human D2 dopamine receptor". Proc. Natl. Acad. Sci. U.S.A. 86 (24): 9762–6. doi:10.1073/pnas.86.24.9762. PMC 298581. PMID 2532362. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=298581. 
• Selbie LA, Hayes G, Shine J (1990). "The major dopamine D2 receptor: molecular analysis of the human D2A subtype". DNA 8 (9): 683–9. PMID 2533064. 
• Leysen JE, Gommeren W, Mertens J, et al. (1995). "Comparison of in vitro binding properties of a series of dopamine antagonists and agonists for cloned human dopamine D2S and D2L receptors and for D2 receptors in rat striatal and mesolimbic tissues, using [125I] 2'-iodospiperone". Psychopharmacology (Berl.) 110 (1–2): 27–36. doi:10.1007/BF02246947. PMID 7870895. 
• Itokawa M, Arinami T, Futamura N, et al. (1994). "A structural polymorphism of human dopamine D2 receptor, D2(Ser311-->Cys)". Biochem. Biophys. Res. Commun. 196 (3): 1369–75. doi:10.1006/bbrc.1993.2404. PMID 7902708. 
• Malmberg A, Jackson DM, Eriksson A, Mohell N (1993). "Unique binding characteristics of antipsychotic agents interacting with human dopamine D2A, D2B, and D3 receptors". Mol. Pharmacol. 43 (5): 749–54. PMID 8099194. 
• Seeman P, Ohara K, Ulpian C, et al. (1993). "Schizophrenia: normal sequence in the dopamine D2 receptor region that couples to G-proteins. DNA polymorphisms in D2". Neuropsychopharmacology 8 (2): 137–42. PMID 8471125. 
• Cravchik A, Sibley DR, Gejman PV (1996). "Functional analysis of the human D2 dopamine receptor missense variants". J. Biol. Chem. 271 (42): 26013–7. doi:10.1074/jbc.271.42.26013. PMID 8824240. 
• Ho MK, Wong YH (1997). "Functional role of amino-terminal serine16 and serine27 of G alphaZ in receptor and effector coupling". J. Neurochem. 68 (6): 2514–22. doi:10.1046/j.1471-4159.1997.68062514.x. PMID 9166747. 
• Centonze D, Gubellini P, "et al." (2004). "Differential contribution of dopamine D2S and D2L receptors in the modulation of glutamate and GABA transmission in the striatum". Neuroscience 129 (1): 157–66. doi:10.1016/j.neuroscience.2004.07.043. PMID 15489038. 

External links

• "Dopamine Receptors: D₂". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2254. 
• Pappas, Stephanie. "Study: Genes Influence Who Your Friends Are". Imaginova Corp.. LiveScience. http://www.livescience.com/health/genes-influence-friendships-110117.html. Retrieved 20 January 2011. 
• MeSH Receptors,+Dopamine+D2

Metabolites and
signaling molecules

Eicosanoid	CysLT (1, 2) · LTB4 (1, 2) · FPRL1 · OXE · Prostaglandin (DP (1, 2), EP (1, 2, 3, 4), FP) · Prostacyclin · Thromboxane
Other	Bile acid · Cannabinoid (CB1, CB2, GPR (18, 55, 119)) · EBI2 · Estrogen · Free fatty acid (1, 2, 3, 4) · Lactate  · Lysophosphatidic acid (1, 2, 3, 4, 5, 6)  · Lysophospholipid (1, 2, 3, 4, 5, 6, 7, 8) · Niacin (1, 2) · Oxoglutarate · PAF · Sphingosine-1-phosphate (1, 2, 3, 4, 5) · Succinate

Peptide

Neuropeptide	B/W (1, 2) · FF (1, 2) · S · Y (1, 2, 4, 5) · Neuromedin (B, U (1, 2)) · Neurotensin (1, 2)
Other	Anaphylatoxin (C3a, C5a) · Angiotensin (1, 2) · Apelin · Bombesin (BRS3, GRPR, NMBR) · Bradykinin (B1, B2) · Chemokine · Cholecystokinin (A, B) · Endothelin (A, B) · Formyl peptide (1, 2, 3) · FSH · Galanin (1, 2, 3) · GHB receptor · Gonadotropin-releasing hormone (1, 2) · Ghrelin · Kisspeptin · Luteinizing hormone/choriogonadotropin · MAS (1, 1L, D, E, F, G, X1, X2, X3, X4) · Melanocortin (1, 2, 3, 4, 5) · MCHR (1, 2) · Motilin · Opioid (Delta, Kappa, Mu, Nociceptin & Zeta, but not Sigma) · Orexin (1, 2) · Oxytocin · Prokineticin (1, 2) · Prolactin-releasing peptide · Relaxin (1, 2, 3, 4) · Somatostatin (1, 2, 3, 4, 5) · Tachykinin (1, 2, 3) · Thyrotropin · Thyrotropin-releasing hormone · Urotensin-II · Vasopressin (1A, 1B, 2)

Miscellaneous

Orphan	GPR (1, 3, 4, 6, 12, 15, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 31, 32, 33, 34, 35, 37, 39, 42, 44, 45, 50, 52, 55, 61, 62, 63, 65, 68, 75, 77, 78, 81, 82, 83, 84, 85, 87, 88, 92, 101, 103, 109A, 109B, 119, 120, 132, 135, 137B, 139, 141, 142, 146, 148, 149, 150, 151, 152, 153, 160, 161, 162, 171, 173, 174, 176, 177, 182, 183)
Other	Adrenomedullin · Olfactory · Opsin (3, 4, 5, 1LW, 1MW, 1SW, RGR, RRH) · Protease-activated (1, 2, 3, 4) · SREB (1, 2, 3)

Class B: Secretin like

Orphan	GPR (56, 64, 97, 98, 110, 111, 112, 113, 114, 115, 116, 123, 124, 125, 126, 128, 133, 143, 144, 155, 157)
Other	Brain-specific angiogenesis inhibitor (1, 2, 3) · Cadherin (1, 2, 3) · Calcitonin · CALCRL · CD97 · Corticotropin-releasing hormone (1, 2) · EMR (1, 2, 3) · Glucagon (GR, GIPR, GLP1R, GLP2R) · Growth hormone releasing hormone · PACAPR1 · GPR · Latrophilin (1, 2, 3, ELTD1) · Methuselah-like proteins · Parathyroid hormone (1, 2) · Secretin · Vasoactive intestinal peptide (1, 2)

Class C: Metabotropic
glutamate / pheromone

Taste	TAS1R (1, 2, 3) · TAS2R (1, 3, 4, 5, 8, 9, 10, 12, 13, 14, 16, 19, 20, 30, 31, 38, 39, 40, 41, 42, 43, 45, 46, 50)
Other	Calcium-sensing receptor · GABA B (1, 2) · Glutamate receptor (Metabotropic glutamate (1, 2, 3, 4, 5, 6, 7, 8)) · GPRC6A · GPR (156, 158, 179) · RAIG (1, 2, 3, 4)

Class F:
Frizzled / Smoothened

Frizzled	Frizzled (1, 2, 3, 4, 5, 6, 7, 8, 9, 10)
Smoothened	Smoothened

B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)