Dopamine receptor D2

{{Short description|Main receptor for most antipsychotic drugs}} {{cs1 config|name-list-style=vanc}} {{DISPLAYTITLE:Dopamine receptor D₂}} {{Use dmy dates|date=October 2020}} {{Infobox_gene}} '''Dopamine receptor D₂''', also known as '''D₂R''', is a protein that, in humans, is encoded by the ''DRD2'' gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon H. Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D₂ receptor.<ref>{{cite journal | vauthors = Madras BK | title = History of the discovery of the antipsychotic dopamine D2 receptor: a basis for the dopamine hypothesis of schizophrenia | journal = Journal of the History of the Neurosciences | volume = 22 | issue = 1 | pages = 62–78 | date = 2013 | pmid = 23323533 | doi = 10.1080/0964704X.2012.678199 | s2cid = 12002684 }}</ref> The dopamine D₂ receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.<ref name="pmid29466326">{{cite journal|author6-link=Bryan Roth | vauthors = Wang S, Che T, Levit A, Shoichet BK, Wacker D, Roth BL | title = Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone | journal = Nature | volume = 555 | issue = 7695 | pages = 269–273 | date = March 2018 | pmid = 29466326 | pmc = 5843546 | doi = 10.1038/nature25758 | bibcode = 2018Natur.555..269W }}</ref><ref>{{Cite web|url=https://www.nimh.nih.gov/news/science-updates/2018/molecular-secrets-revealed-antipsychotic-docked-in-its-receptor|title=NIMH » Molecular Secrets Revealed: Antipsychotic Docked in its Receptor|website=www.nimh.nih.gov|date=29 January 2018 |language=en|access-date=2018-11-26}}</ref>

== Function == D₂ receptors are coupled to the G_i subtype of G protein. This G protein-coupled receptor inhibits adenylyl cyclase activity.<ref name="pmid11089973">{{cite journal | vauthors = Usiello A, Baik JH, Rougé-Pont F, Picetti R, Dierich A, LeMeur M, Piazza PV, Borrelli E | title = Distinct functions of the two isoforms of dopamine D2 receptors | journal = Nature | volume = 408 | issue = 6809 | pages = 199–203 | date = November 2000 | pmid = 11089973 | doi = 10.1038/35041572 | bibcode = 2000Natur.408..199U | s2cid = 4354606 }}</ref>

In mice, regulation of D₂R surface expression by the neuronal calcium sensor-1 (NCS-1) in the dentate gyrus is involved in exploration, synaptic plasticity and memory formation.<ref name="pmid19755107">{{cite journal | vauthors = Saab BJ, Georgiou J, Nath A, Lee FJ, Wang M, Michalon A, Liu F, Mansuy IM, Roder JC | title = NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory | journal = Neuron | volume = 63 | issue = 5 | pages = 643–56 | date = September 2009 | pmid = 19755107 | doi = 10.1016/j.neuron.2009.08.014 | s2cid = 5321020 | doi-access = free }}</ref> Studies have shown potential roles for D₂R in retrieval of fear memories in the prelimbic cortex<ref>{{cite journal | vauthors = Madsen HB, Guerin AA, Kim JH | title = Investigating the role of dopamine receptor- and parvalbumin-expressing cells in extinction of conditioned fear | journal = Neurobiology of Learning and Memory | volume = 145 | pages = 7–17 | date = November 2017 | pmid = 28842281 | doi = 10.1016/j.nlm.2017.08.009 | s2cid = 26875742 }}</ref> and in discrimination learning in the nucleus accumbens.<ref>{{cite journal | vauthors = Iino Y, Sawada T, Yamaguchi K, Tajiri M, Ishii S, Kasai H, Yagishita S | title = Dopamine D2 receptors in discrimination learning and spine enlargement | journal = Nature | volume = 579 | issue = 7800 | pages = 555–560 | date = March 2020 | pmid = 32214250 | doi = 10.1038/s41586-020-2115-1 | bibcode = 2020Natur.579..555I | s2cid = 213162661 | url = https://www.nature.com/articles/s41586-020-2115-1 | url-access = subscription }}</ref>

In flies, activation of the D₂ autoreceptor protected dopamine neurons from cell death induced by MPP⁺, a toxin mimicking Parkinson's disease pathology.<ref name="pmid23452092">{{cite journal | vauthors = Wiemerslage L, Schultz BJ, Ganguly A, Lee D | title = Selective degeneration of dopaminergic neurons by MPP(+) and its rescue by D2 autoreceptors in Drosophila primary culture | journal = Journal of Neurochemistry | volume = 126 | issue = 4 | pages = 529–40 | date = August 2013 | pmid = 23452092 | pmc = 3737274 | doi = 10.1111/jnc.12228 }}</ref>

While optimal dopamine levels favor D₁R cognitive stabilization, it is the D₂R that mediates the cognitive flexibility in humans.<ref>{{cite journal | vauthors = Cameron IG, Wallace DL, Al-Zughoul A, Kayser AS, D'Esposito M | title = Effects of tolcapone and bromocriptine on cognitive stability and flexibility | journal = Psychopharmacology | volume = 235 | issue = 4 | pages = 1295–1305 | date = April 2018 | pmid = 29427081 | pmc = 5869902 | doi = 10.1007/s00213-018-4845-4 | department = primary }}</ref><ref>{{cite journal | vauthors = Yee DM, Braver TS | title = Interactions of Motivation and Cognitive Control | journal = Current Opinion in Behavioral Sciences | volume = 19 | pages = 83–90 | date = February 2018 | pmid = 30035206 | pmc = 6051692 | doi = 10.1016/j.cobeha.2017.11.009 }}</ref><ref>{{cite journal | vauthors = Persson J, Stenfors C | title = Superior cognitive goal maintenance in carriers of genetic markers linked to reduced striatal D2 receptor density (C957T and DRD2/ANKK1-TaqIA) | journal = PLOS ONE| volume = 13 | issue = 8 | article-number = e0201837 | date = 2018 | pmid = 30125286 | pmc = 6101371 | doi = 10.1371/journal.pone.0201837 | bibcode = 2018PLoSO..1301837P | doi-access = free }}</ref>

== Isoforms{{anchor|D2sh}} ==

Alternative splicing of this gene results in three transcript variants encoding different isoforms.<ref name="entrez">{{cite web | title = Entrez Gene: DRD2 dopamine receptor D2| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=1813 }}</ref>

The long form ('''D2Lh''') has the "canonical" sequence and functions as a classic post-synaptic receptor.<ref name="D2 Long and short">{{cite journal | vauthors = Beaulieu JM, Gainetdinov RR | title = The physiology, signaling, and pharmacology of dopamine receptors | journal = Pharmacological Reviews | volume = 63 | issue = 1 | pages = 182–217 | date = March 2011 | pmid = 21303898 | doi = 10.1124/pr.110.002642 | s2cid = 2545878 }}</ref> The short form ('''D2Sh''') is pre-synaptic and functions as an autoreceptor that regulates the levels of dopamine in the synaptic cleft.<ref name="D2 Long and short" /> Agonism of D2sh receptors inhibits dopamine release; antagonism increases dopaminergic release.<ref name="D2 Long and short" /> A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ.<ref name = "uniprot">{{UniProt Full|P14416|D(2) dopamine receptor}}</ref>

== Active and inactive forms == D₂R conformers are equilibrated between two full active (D₂^''High''R) and inactive (D₂^''Low''R) states, while in complex with an agonist and antagonist ligand, respectively.

The monomeric inactive conformer of D₂R in binding with risperidone was reported in 2018 (PDB ID: 6CM4). However, the active form which is generally bound to an agonist, is not available yet and in most of the studies the homology modeling of the structure is implemented. The difference between the active and inactive of G protein-coupled receptor is mainly observed as conformational changes at the cytoplasmic half of the structure, particularly at the transmembrane domains (TM) 5 and 6. The conformational transitions occurred at the cytoplasmic ends are due to the coupling of G protein to the cytoplasmic loop between the TM 5 and 6.<ref>{{cite journal | vauthors = Salmas RE, Yurtsever M, Stein M, Durdagi S | title = Modeling and protein engineering studies of active and inactive states of human dopamine D2 receptor (D2R) and investigation of drug/receptor interactions | journal = Molecular Diversity | volume = 19 | issue = 2 | pages = 321–32 | date = May 2015 | pmid = 25652238 | doi = 10.1007/s11030-015-9569-3 | s2cid = 1636767 }}</ref>

It was observed that either D₂R agonist or antagonist ligands revealed better binding affinities inside the ligand-binding domain of the active D₂R in comparison with the inactive state. It demonstrated that ligand-binding domain of D₂R is affected by the conformational changes occurring at the cytoplasmic domains of the TM 5 and 6. In consequence, the D₂R activation reflects a positive cooperation on the ligand-binding domain.

In drug discovery studies in order to calculate the binding affinities of the D₂R ligands inside the binding domain, it's important to work on which form of D₂R. It's known that the full active and inactive states are recommended to be used for the agonist and antagonist studies, respectively.

Any disordering in equilibration of D₂R states, which causes problems in signal transferring between the nervous systems, may lead to diverse serious disorders, such as schizophrenia,<ref>{{cite journal | vauthors = Seeman P, Chau-Wong M, Tedesco J, Wong K | title = Brain receptors for antipsychotic drugs and dopamine: direct binding assays | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 72 | issue = 11 | pages = 4376–80 | date = November 1975 | pmid = 1060115 | pmc = 388724 | doi = 10.1073/pnas.72.11.4376 | bibcode = 1975PNAS...72.4376S | doi-access = free }}</ref> autism{{citation needed|date=February 2024}} and Parkinson's disease.{{citation needed|date=February 2024}} In order to assist in the management of these conditions, equilibration between the D₂R states is controlled by implementing of agonist and antagonist D₂R ligands.{{citation needed|date=February 2024}} In most cases, it was observed that the problems regarding the D₂R states may have genetic roots and are controlled by drug therapies.{{citation needed|date=February 2024}} So far, there is no certain treatment for these mental disorders.

== Allosteric pocket and orthosteric pocket == There is an orthosteric binding site (OBS), as well as a secondary binding pocket (SBP) on the dopamine 2 receptor, and interaction with the SBP is a requirement for allosteric pharmacology. The compound SB269652 is a negative allosteric modulator of the D₂R.<ref>{{cite journal | vauthors = Draper-Joyce CJ, Michino M, Verma RK, Klein Herenbrink C, Shonberg J, Kopinathan A, Scammells PJ, Capuano B, Thal DM, Javitch JA, Christopoulos A, Shi L, Lane JR | title = 2 receptor | journal = Biochemical Pharmacology | volume = 148 | pages = 315–328 | date = February 2018 | pmid = 29325769 | pmc = 5800995 | doi = 10.1016/j.bcp.2018.01.002 }}</ref>

== Oligomerization of D₂R == It was observed that D₂R exists in dimeric forms or higher order oligomers.<ref>{{cite journal | vauthors = Armstrong D, Strange PG | title = Dopamine D2 receptor dimer formation: evidence from ligand binding | journal = The Journal of Biological Chemistry | volume = 276 | issue = 25 | pages = 22621–9 | date = June 2001 | pmid = 11278324 | doi = 10.1074/jbc.M006936200 | doi-access = free }}</ref> There are some experimental and molecular modeling evidences that demonstrated the D₂R monomers cross link from their TM 4 and TM 5 to form dimeric conformers.<ref>{{cite journal | vauthors = Guo W, Shi L, Javitch JA | title = The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer | journal = The Journal of Biological Chemistry | volume = 278 | issue = 7 | pages = 4385–8 | date = February 2003 | pmid = 12496294 | doi = 10.1074/jbc.C200679200 |doi-access=free }}</ref><ref>{{cite journal | vauthors = Durdagi S, Salmas RE, Stein M, Yurtsever M, Seeman P | title = Binding Interactions of Dopamine and Apomorphine in D2High and D2Low States of Human Dopamine D2 Receptor Using Computational and Experimental Techniques | language = EN | journal = ACS Chemical Neuroscience | volume = 7 | issue = 2 | pages = 185–95 | date = February 2016 | pmid = 26645629 | doi = 10.1021/acschemneuro.5b00271 }}</ref>

== Genetics == Allelic variants: * A-241G * C132T, G423A, T765C, C939T, C957T, and G1101A<ref name="pmid12554675">{{cite journal | vauthors = Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV | title = Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor | journal = Human Molecular Genetics | volume = 12 | issue = 3 | pages = 205–16 | date = February 2003 | pmid = 12554675 | doi = 10.1093/hmg/ddg055 | doi-access = free }}</ref> * Cys311Ser * -141C insertion/deletion<ref name="pmid9097961">{{cite journal | vauthors = Arinami T, Gao M, Hamaguchi H, Toru M | title = A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia | journal = Human Molecular Genetics | volume = 6 | issue = 4 | pages = 577–82 | date = April 1997 | pmid = 9097961 | doi = 10.1093/hmg/6.4.577 | doi-access = free }}</ref> The polymorphisms have been investigated with respect to association with schizophrenia.<ref name="pmid15211624">{{cite journal | vauthors = Glatt SJ, Faraone SV, Tsuang MT | title = DRD2 -141C insertion/deletion polymorphism is not associated with schizophrenia: results of a meta-analysis | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 128B | issue = 1 | pages = 21–3 | date = July 2004 | pmid = 15211624 | doi = 10.1002/ajmg.b.30007 | s2cid = 330601 }}</ref>

Some researchers have previously associated the polymorphism Taq 1A (rs1800497) to the ''DRD2'' gene. However, the polymorphism resides in exon 8 of the ''ANKK1'' gene.<ref name="pmid18621654">{{cite journal | vauthors = Lucht M, Rosskopf D | title = Comment on "Genetically determined differences in learning from errors" | journal = Science | volume = 321 | issue = 5886 | pages = 200; author reply 200 | date = July 2008 | pmid = 18621654 | doi = 10.1126/science.1155372 | bibcode = 2008Sci...321..200L | s2cid = 263582444 | doi-access = }}</ref> DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor fluctuations but not hallucinations in Parkinson's disease.<ref name="pmid11425949">{{cite journal | vauthors = Wang J, Liu ZL, Chen B | title = Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD | journal = Neurology | volume = 56 | issue = 12 | pages = 1757–9 | date = June 2001 | pmid = 11425949 | doi = 10.1212/WNL.56.12.1757 | s2cid = 38421055 }}</ref><ref name="Wang J, Zhao c, Chen B, Liu Z. 2004">{{cite journal | vauthors = Wang J, Zhao C, Chen B, Liu ZL | title = Polymorphisms of dopamine receptor and transporter genes and hallucinations in Parkinson's disease | journal = Neuroscience Letters | volume = 355 | issue = 3 | pages = 193–6 | date = January 2004 | pmid = 14732464 | doi = 10.1016/j.neulet.2003.11.006 | s2cid = 44740438 }}</ref> A splice variant in Dopamine receptor D2(rs1076560) was found to be associated with limb truncal tardive dyskinesia and diminished expression factor of Positive and Negative Syndrome Scale (PANSS) in schizophrenia subjects.<ref name="pmid32931693">{{cite journal | vauthors = Punchaichira TJ, Kukshal P, Bhatia T, Deshpande SN, Thelma BK |title = The effect of rs1076560 (DRD2) and rs4680 (COMT) on tardive dyskinesia and cognition in schizophrenia subjects|journal = Psychiatric Genetics | volume = 30 | issue = 5 | pages = 125–135 | year = 2020 | pmid = 32931693 | doi = 10.1097/YPG.0000000000000258|s2cid = 221718209| pmc = 10111058 }}</ref>

== 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=== {{div col|colwidth=33em}} * Bromocriptine – full agonist * Cabergoline (Dostinex) * N,N-Propyldihydrexidine – analogue of the D₁/D₅ agonist dihydrexidine; Selective for postsynaptic D₂ receptor over the presynaptic D₂ autoreceptor. * Piribedil – also D₃ receptor agonist and α₂–adrenergic antagonist * Pramipexole – also D₃, D₄ receptor agonist * Quinagolide (Norprolac) * Quinelorane – affinity for D₂ > D₃ * Quinpirole – also D₃ receptor agonist * Ropinirole – full agonist * Sumanirole – full agonist; highly selective * Talipexole – selective for D₂ over other dopamine receptors, but also acts as α₂–adrenoceptor agonist and 5-HT₃ antagonist. {{Div col end}}

===Partial agonists=== {{div col|colwidth=33em}} * Aplindore * Aripiprazole<ref name="Rxlist - Abilify">{{cite web | url = http://www.rxlist.com/abilify-drug.htm | title = Clinical Pharmacology for Abilify | date = 2010-01-21 | publisher = RxList.com | access-date = 2010-01-21}}</ref> * Armodafinil – although primarily thought to be a weak DAT inhibitor, armodafinil is also a D₂ partial agonist.<ref name="pmid19391150">{{cite journal | vauthors = Seeman P, Guan HC, Hirbec H | title = Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil | journal = Synapse | volume = 63 | issue = 8 | pages = 698–704 | date = August 2009 | pmid = 19391150 | doi = 10.1002/syn.20647 | s2cid = 17758902 }}</ref> * Modafinil - The (R)-(−)-enantiomer, known as Armodafinil in its pure form<ref name="pmid19391150"/> * Brexpiprazole * Cariprazine * Cannabidiol * GSK-789,472 – Also D₃ antagonist, with good selectivity over other receptors<ref name="pmid20153647">{{cite journal | vauthors = 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 | title = The identification of a selective dopamine D2 partial agonist, D3 antagonist displaying high levels of brain exposure | journal = Bioorganic & Medicinal Chemistry Letters | volume = 20 | issue = 6 | pages = 2013–6 | date = March 2010 | pmid = 20153647 | doi = 10.1016/j.bmcl.2010.01.090 }}</ref> * Ketamine (also NMDA antagonist) * LSD – in vitro, LSD was found to be a partial agonist and potentiates dopamine-mediated prolactin secretion in lactotrophs.<ref name="pmid9698051">{{cite journal | vauthors = Giacomelli S, Palmery M, Romanelli L, Cheng CY, Silvestrini B | title = Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro | journal = Life Sciences | volume = 63 | issue = 3 | pages = 215–22 | year = 1998 | pmid = 9698051 | doi = 10.1016/S0024-3205(98)00262-8 }}</ref> LSD is also a 5-HT_2A agonist. * OSU-6162 – also 5-HT_2A partial agonist, acts as "dopamine stabilizer" * Roxindole (only at the D₂ autoreceptors) * Brilaroxazine(RP5063) * Salvinorin A – also κ-opioid agonist. * Memantine – Also NMDA antagonist<ref name="pmid18000814">{{cite journal | vauthors = Seeman P, Caruso C, Lasaga M | title = Memantine agonist action at dopamine D2High receptors | journal = Synapse | volume = 62 | issue = 2 | pages = 149–53 | date = February 2008 | pmid = 18000814 | doi = 10.1002/syn.20472 | s2cid = 20494427 | hdl = 11336/108388 | hdl-access = free }}</ref><ref name="Sani Serra Kotzalidis Romano 2012 pp. 663–690">{{cite journal | vauthors = Sani G, Serra G, Kotzalidis GD, Romano S, Tamorri SM, Manfredi G, Caloro M, Telesforo CL, Caltagirone SS, Panaccione I, Simonetti A, Demontis F, Serra G, Girardi P | display-authors = 6 | title = The role of memantine in the treatment of psychiatric disorders other than the dementias: a review of current preclinical and clinical evidence | journal = CNS Drugs | volume = 26 | issue = 8 | pages = 663–90 | date = August 2012 | pmid = 22784018 | doi = 10.2165/11634390-000000000-00000 | s2cid = 21597978 }}</ref> {{Div col end}}

===Antagonists=== {{div col|colwidth=33em}} * Atypical antipsychotics (except aripiprazole, brexpiprazole, and any other D₂ receptor partial agonists) * Cinnarizine * Chloroethylnorapomorphine * Desmethoxyfallypride * Domperidone – D₂ and D₃ antagonist; does not cross the blood-brain barrier * Mesdopetam * Metoclopramide – Antiemetic, crosses blood-brain barrier. Causes drug-induced Parkinsonism. * Eticlopride * Fallypride * Hydroxyzine (Vistaril, Atarax) * Itopride - does not cross the blood-brain barrier * L-741,626 – 4-phenylpiperidine (similar to haloperidol), highly selective D₂ inverse agonist * ST-148 (D2L antagonist) - D2L selective antagonist * ¹¹C-radiolabeled Raclopride – commonly employed in positron emission tomography studies<ref name="pmid15256343">{{cite journal | vauthors = Wang GJ, Volkow ND, Thanos PK, Fowler JS | title = Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review | journal = Journal of Addictive Diseases | volume = 23 | issue = 3 | pages = 39–53 | year = 2004 | pmid = 15256343 | doi = 10.1300/J069v23n03_04 | s2cid = 14589783 }}</ref> * Typical antipsychotics * SV 293<ref>{{cite journal | vauthors = Huang R, Griffin SA, Taylor M, Vangveravong S, Mach RH, Dillon GH, Luedtke RR | title = The effect of SV 293, a D2 dopamine receptor-selective antagonist, on D2 receptor-mediated GIRK channel activation and adenylyl cyclase inhibition | journal = Pharmacology | volume = 92 | issue = 1–2 | pages = 84–9 | year = 2013 | pmid = 23942137 | doi = 10.1159/000351971 | s2cid = 33761631 | pmc = 12013381 }}</ref> * Yohimbine * Buspirone{{snd}} D₂ presynaptic autoreceptors (low dose) and postsynaptic D₂ receptors (at higher doses) antagonist<ref>{{cite journal | vauthors = Lechin F, van der Dijs B, Jara H, Orozco B, Baez S, Benaim M, Lechin M, Lechin A | title = Effects of buspirone on plasma neurotransmitters in healthy subjects | journal = Journal of Neural Transmission | volume = 105 | issue = 6–7 | pages = 561–73 | date = 1998 | pmid = 9826102 | doi = 10.1007/s007020050079 | s2cid = 12858061 }}</ref>

;D₂sh selective (presynaptic autoreceptors) * Amisulpride (low doses) * CGP-25454A * Sulpiride * UH-232 {{Div col end}}

===Allosteric modulators=== {{div col|colwidth=33em}} * Homocysteine – negative allosteric modulator<ref>{{cite journal | vauthors = Agnati LF, Ferré S, Genedani S, Leo G, Guidolin D, Filaferro M, Carriba P, Casadó V, Lluis C, Franco R, Woods AS, Fuxe K | title = Allosteric modulation of dopamine D2 receptors by homocysteine | journal = Journal of Proteome Research | volume = 5 | issue = 11 | pages = 3077–83 | date = November 2006 | pmid = 17081059 | doi = 10.1021/pr0601382 | citeseerx = 10.1.1.625.26 }}</ref> * PAOPA<ref>{{cite journal | vauthors = Beyaert MG, Daya RP, Dyck BA, Johnson RL, Mishra RK | title = PAOPA, a potent dopamine D2 receptor allosteric modulator, prevents and reverses behavioral and biochemical abnormalities in an amphetamine-sensitized preclinical animal model of schizophrenia | journal = European Neuropsychopharmacology | volume = 23 | issue = 3 | pages = 253–62 | date = March 2013 | pmid = 22658400 | doi = 10.1016/j.euroneuro.2012.04.010 | s2cid = 25146332 }}</ref> * SB269652<ref name="pmid25108820">{{cite journal | vauthors = Lane JR, Donthamsetti P, Shonberg J, Draper-Joyce CJ, Dentry S, Michino M, Shi L, López L, Scammells PJ, Capuano B, Sexton PM, Javitch JA, Christopoulos A | title = A new mechanism of allostery in a G protein-coupled receptor dimer | journal = Nature Chemical Biology | volume = 10 | issue = 9 | pages = 745–52 | date = September 2014 | pmid = 25108820 | pmc = 4138267 | doi = 10.1038/nchembio.1593 }}</ref><ref name="pmid25453482">{{cite journal | vauthors = Maggio R, Scarselli M, Capannolo M, Millan MJ | title = Novel dimensions of D3 receptor function: Focus on heterodimerisation, transactivation and allosteric modulation | journal = European Neuropsychopharmacology | volume = 25 | issue = 9 | pages = 1470–9 | date = September 2015 | pmid = 25453482 | doi = 10.1016/j.euroneuro.2014.09.016 | s2cid = 25513707 }}</ref><ref>{{cite journal | vauthors = Silvano E, Millan MJ, Mannoury la Cour C, Han Y, Duan L, Griffin SA, Luedtke RR, Aloisi G, Rossi M, Zazzeroni F, Javitch JA, Maggio R | title = The tetrahydroisoquinoline derivative SB269,652 is an allosteric antagonist at dopamine D3 and D2 receptors | journal = Molecular Pharmacology | volume = 78 | issue = 5 | pages = 925–34 | date = November 2010 | pmid = 20702763 | pmc = 2981362 | doi = 10.1124/mol.110.065755 }}</ref><ref>{{cite journal | vauthors = Rossi M, Fasciani I, Marampon F, Maggio R, Scarselli M | title = 3 Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs | journal = Molecular Pharmacology | volume = 91 | issue = 6 | pages = 586–594 | date = June 2017 | pmid = 28265019 | pmc = 5438131 | doi = 10.1124/mol.116.107607 }}</ref> {{Div col end}}

=== Heterobivalent ligands === * 1-(6-(((''R'',''S'')-7-Hydroxychroman-2-yl)methylamino]hexyl)-3-((''S'')-1-methylpyrrolidin-2-yl)pyridinium bromide (compound 2, D2R agonist and nAChR antagonist)<ref>{{cite journal | vauthors = Matera C, Pucci L, Fiorentini C, Fucile S, Missale C, Grazioso G, Clementi F, Zoli M, De Amici M, Gotti C, Dallanoce C | title = Bifunctional compounds targeting both D2 and non-α7 nACh receptors: design, synthesis and pharmacological characterization | journal = European Journal of Medicinal Chemistry | volume = 101 | pages = 367–83 | date = August 2015 | pmid = 26164842 | doi = 10.1016/j.ejmech.2015.06.039 | hdl = 11380/1134176 | hdl-access = free }}</ref>

=== Dual D₂AR/ A_2AAR ligands === * Dual agonists for A_2AAR and D2AR receptors have been developed.<ref>{{cite journal | vauthors = Kampen S, Duy Vo D, Zhang X, Panel N, Yang Y, Jaiteh M, Matricon P, Svenningsson P, Brea J, Loza MI, Kihlberg J, Carlsson J | display-authors = 6 | title = Structure-Guided Design of G-Protein-Coupled Receptor Polypharmacology | journal = Angewandte Chemie | volume = 60 | issue = 33 | pages = 18022–18030 | date = August 2021 | pmid = 33904641 | pmc = 8456950 | doi = 10.1002/anie.202101478 }}</ref>

=== Functionally selective ligands === * UNC9994<ref>{{cite journal | vauthors = Allen JA, Yost JM, Setola V, Chen X, Sassano MF, Chen M, Peterson S, Yadav PN, Huang XP, Feng B, Jensen NH, Che X, Bai X, Frye SV, Wetsel WC, Caron MG, Javitch JA, Roth BL, Jin J | title = Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 45 | pages = 18488–93 | date = November 2011 | pmid = 22025698 | pmc = 3215024 | doi = 10.1073/pnas.1104807108 | bibcode = 2011PNAS..10818488A | doi-access = free }}</ref>

==Protein–protein interactions== The dopamine receptor D₂ has been shown to interact with EPB41L1,<ref name="pmid12181426">{{cite journal | vauthors = Binda AV, Kabbani N, Lin R, Levenson R | title = D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1N | journal = Molecular Pharmacology | volume = 62 | issue = 3 | pages = 507–13 | date = September 2002 | pmid = 12181426 | doi = 10.1124/mol.62.3.507 | s2cid = 19901660 }}</ref> PPP1R9B<ref name="pmid10391935">{{cite journal | vauthors = Smith FD, Oxford GS, Milgram SL | title = Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting protein | journal = The Journal of Biological Chemistry | volume = 274 | issue = 28 | pages = 19894–900 | date = July 1999 | pmid = 10391935 | doi = 10.1074/jbc.274.28.19894 | doi-access = free }}</ref> and NCS-1.<ref name="pmid12351722">{{cite journal | vauthors = Kabbani N, Negyessy L, Lin R, Goldman-Rakic P, Levenson R | title = Interaction with neuronal calcium sensor NCS-1 mediates desensitization of the D2 dopamine receptor | journal = The Journal of Neuroscience | volume = 22 | issue = 19 | pages = 8476–86 | date = October 2002 | pmid = 12351722 | pmc = 6757796 | doi = 10.1523/JNEUROSCI.22-19-08476.2002 }}</ref>

===Receptor oligomers=== The D₂ receptor forms receptor heterodimers ''in vivo'' (i.e., in living animals) with other G protein-coupled receptors; these include:<ref name="DA receptor heterodimers">{{cite journal | vauthors = Beaulieu JM, Espinoza S, Gainetdinov RR | title = Dopamine receptors – IUPHAR Review 13 | journal = British Journal of Pharmacology | volume = 172 | issue = 1 | pages = 1–23 | date = January 2015 | pmid = 25671228 | pmc = 4280963 | doi = 10.1111/bph.12906 }}</ref> *D₁–D₂ dopamine receptor heteromer *D₂–adenosine A_2A *D₂–ghrelin receptor *D_2sh–TAAR1{{#tag:ref|D2sh–TAAR1 is a presynaptic heterodimer which involves the relocation of TAAR1 from the intracellular space to D2sh at the plasma membrane, increased D2sh agonist binding affinity, and signal transduction through the calcium–PKC–NFAT pathway and G-protein independent PKB–GSK3 pathway.<ref name="Miller+Grandy 2016">{{cite journal | vauthors = Grandy DK, Miller GM, Li JX | title = "TAARgeting Addiction"--The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference | journal = Drug and Alcohol Dependence | volume = 159 | pages = 9–16 | date = February 2016 | pmid = 26644139 | pmc = 4724540 | doi = 10.1016/j.drugalcdep.2015.11.014 | quote = This original observation of TAAR1 and DA D2R interaction has subsequently been confirmed and expanded upon with observations that both receptors can heterodimerize with each other under certain conditions&nbsp;... Additional DA D2R/TAAR1 interactions with functional consequences are revealed by the results of experiments demonstrating that in addition to the cAMP/PKA pathway (Panas et al., 2012) stimulation of TAAR1-mediated signaling is linked to activation of the Ca++/PKC/NFAT pathway (Panas et al.,2012) and the DA D2R-coupled, G protein-independent AKT/GSK3 signaling pathway (Espinoza et al., 2015; Harmeier et al., 2015), such that concurrent TAAR1 and DA DR2R activation could result in diminished signaling in one pathway (e.g. cAMP/PKA) but retention of signaling through another (e.g., Ca++/PKC/NFA) }}</ref><ref name="TAAR1-D2sh">{{cite journal | vauthors = Harmeier A, Obermueller S, Meyer CA, Revel FG, Buchy D, Chaboz S, Dernick G, Wettstein JG, Iglesias A, Rolink A, Bettler B, Hoener MC | title = Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers | journal = European Neuropsychopharmacology | volume = 25 | issue = 11 | pages = 2049–61 | date = November 2015 | pmid = 26372541 | doi = 10.1016/j.euroneuro.2015.08.011 | s2cid = 41667764 | quote = Interaction of TAAR1 with D2R altered the subcellular localization of TAAR1 and increased D2R agonist binding affinity. }}</ref>|group="note"}}

The D₂ receptor has been shown to form heterodimers ''in vitro'' (and possibly ''in vivo'') with DRD₃,<ref>{{cite journal | vauthors = Maggio R, Millan MJ | title = Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance | journal = Current Opinion in Pharmacology | volume = 10 | issue = 1 | pages = 100–7 | date = February 2010 | pmid = 19896900 | doi = 10.1016/j.coph.2009.10.001 }}</ref> DRD₅,<ref>{{cite journal | vauthors = Hasbi A, O'Dowd BF, George SR | title = Heteromerization of dopamine D2 receptors with dopamine D1 or D5 receptors generates intracellular calcium signaling by different mechanisms | journal = Current Opinion in Pharmacology | volume = 10 | issue = 1 | pages = 93–9 | date = February 2010 | pmid = 19897420 | pmc = 2818238 | doi = 10.1016/j.coph.2009.09.011 }}</ref> and 5-HT_2A.<ref>{{cite journal | vauthors = Albizu L, Holloway T, González-Maeso J, Sealfon SC | title = Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors | journal = Neuropharmacology | volume = 61 | issue = 4 | pages = 770–7 | date = September 2011 | pmid = 21645528 | pmc = 3556730 | doi = 10.1016/j.neuropharm.2011.05.023 }}</ref>

== See also == * Prolactin modulator

== Explanatory notes== {{Reflist|group=note}}

== References == {{reflist}}

== External links == * {{MeshName|Receptors,+Dopamine+D2}} * {{cite web | vauthors = Pappas S |title=Study: Genes Influence Who Your Friends Are |url= http://www.livescience.com/health/genes-influence-friendships-110117.html |work=Imaginova Corp. |date=17 January 2011 |publisher=LiveScience |access-date=20 January 2011}}

{{NLM content}} {{G protein-coupled receptors}} {{Dopaminergics}}

Category:Dopamine receptors Category:Biology of attention deficit hyperactivity disorder