Dopamine receptor D2
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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 Snyder and Philip Seeman) used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. 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.
This gene encodes the D2 subtype of the dopamine receptor, which is coupled to Gi subtype of G protein-coupled receptor. This G protein-coupled receptor inhibits adenylyl cyclase activity.
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. A recent study has shown a potential role for D2R in retrieval of fear memories in the prelimbic cortex.
In flies, activation of the D2 autoreceptor protected dopamine neurons from cell death induced by MPP+, a toxin mimicking Parkinson's disease pathology.
Alternative splicing of this gene results in three transcript variants encoding different isoforms.
The long form (D2Lh) has the "canonical" sequence and functions as a classic post-synaptic receptor. The short form (D2Sh) is pre-synaptic and functions as an autoreceptor that regulates the levels of dopamine in the synaptic cleft. Agonism of D2sh receptors inhibits dopamine release; antagonism increases dopaminergic release. A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ.
Active (D2HighR) and inactive (D2LowR) forms
D2R conformers are equilibrated between two full active (D2HighR) and inactive (D2LowR) 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.
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, autism and Parkinson's disease. In order to control these disorders, equilibration between the D2R states is controlled by implementing of agonist and antagonist D2R ligands. In most cases, it was observed that the problems regarding the D2R states may have genetic roots and are controlled by drug therapies. So far, there is no any certain treatment for these mental disorders.
Oligomerization of D2R
It was observed that D2R exists in dimeric forms or higher order oligomers. 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. Oligomerization of D2R has a main role in their biological activities and any disordering in it may lead to mental diseases. It's known that the D2R ligands (either the agonist or antagonist) binding to the ligand-binding domain of D2R are independent of oligomerization and can not have any effect on its process, so the drugs used for the treatment of mental diseases can't cause any main problem in oligomerization of D2R. Since the process of oligomerization of D2R in human bodies and their links to the mental diseases were not explicitly studied, there is no any treatment reported for the disorders originates from oligomerization's problems.
The oligomerization of GPCRs is a controversial topic that there are many unknown problems on this area yet. There's not any crystallographic data available describing the crosslinking of monomers. There are some evidences suggesting that GPCRs monomers crosslinking domains are different and dependent to the biological environments and other factors.
- C132T, G423A, T765C, C939T, C957T, and G1101A
- -141C insertion/deletion The polymorphisms have been investigated with respect to association with schizophrenia.
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. DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor fluctuations but not hallucinations in Parkinson's disease.
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.
- 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
- 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.
- Armodafinil – although primarily thought to be a weak DAT inhibitor, armodafinil is also a D2 partial agonist.
- GSK-789,472 – Also D3 antagonist, with good selectivity over other receptors 
- Ketamine (also NMDA antagonist)
- 2-Phenethylamine – (also a TAAR1 agonist and GABAb antagonist with effects at AMPA receptors)
- LSD – in vitro, LSD was found to be a partial agonist and potentiates dopamine-mediated prolactin secretion in lactotrophs. LSD is also a 5-HT2A agonist.
- OSU-6162 – also 5-HT2A partial agonist, acts as "dopamine stabilizer"
- Roxindole (only at the D2 autoreceptors)
- Salvinorin A – also κ-opioid agonist.
- Atypical antipsychotics (except aripiprazole, brexpiprazole, and any other D2 receptor partial agonists)
- Domperidone – D2 and D3 antagonist; does not cross the blood-brain barrier
- Metoclopramide - Antiemetic - crosses Blood-brain Barrier - causes drug induced Parkinsonism.
- Hydroxyzine (Vistaril, Atarax)
- L-741,626 – highly selective D2 antagonist
- C11 Raclopride radiolabled – commonly employed in positron emission tomography studies
- Typical antipsychotics
- SV 293
- Buspirone D2 presynaptic autoreceptors (low dose) and postsynaptic D2 receptors (at higher doses) antagonist
- D2sh selective (presynaptic autoreceptors)
- Amisulpride (low doses)
- Homocysteine – negative allosteric modulator
- SB-269,652 
- 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)
Functionally selective ligands
The dopamine receptor D2 has been shown to interact with EPB41L1, PPP1R9B and NCS-1.
The D2 receptor forms receptor heterodimers in vivo (i.e., in living animals) with other G protein-coupled receptors; these include:
The D2 receptor has been shown to form hetorodimers in vitro (and possibly in vivo) with DRD3, DRD5, and 5-HT2A.
- ↑ 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.
- ↑ Madras BK (2013). "History of the discovery of the antipsychotic dopamine D2 receptor: a basis for the dopamine hypothesis of schizophrenia". Journal of the History of the Neurosciences. 22 (1): 62–78. doi:10.1080/0964704X.2012.678199. PMID 23323533.
- ↑ Wang S, Che T, Levit A, Shoichet BK, Wacker D, Roth BL (March 2018). "Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone". Nature. 555 (7695): 269–273. doi:10.1038/nature25758. PMC 5843546. PMID 29466326.
- ↑ "NIMH » Molecular Secrets Revealed: Antipsychotic Docked in its Receptor". www.nimh.nih.gov. Retrieved 2018-11-26.
- ↑ Usiello A, Baik JH, Rougé-Pont F, Picetti R, Dierich A, LeMeur M, Piazza PV, Borrelli E (November 2000). "Distinct functions of the two isoforms of dopamine D2 receptors". Nature. 408 (6809): 199–203. doi:10.1038/35041572. PMID 11089973.
- ↑ Saab BJ, Georgiou J, Nath A, Lee FJ, Wang M, Michalon A, Liu F, Mansuy IM, Roder JC (September 2009). "NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory". Neuron. 63 (5): 643–56. doi:10.1016/j.neuron.2009.08.014. PMID 19755107.
- ↑ Madsen HB, Guerin AA, Kim JH (November 2017). "Investigating the role of dopamine receptor- and parvalbumin-expressing cells in extinction of conditioned fear". Neurobiology of Learning and Memory. 145: 7–17. doi:10.1016/j.nlm.2017.08.009. PMID 28842281.
- ↑ Wiemerslage L, Schultz BJ, Ganguly A, Lee D (August 2013). "Selective degeneration of dopaminergic neurons by MPP(+) and its rescue by D2 autoreceptors in Drosophila primary culture". Journal of Neurochemistry. 126 (4): 529–40. doi:10.1111/jnc.12228. PMC 3737274. PMID 23452092.
- ↑ "Entrez Gene: DRD2 dopamine receptor D2".
- ↑ 9.0 9.1 9.2 Beaulieu JM, Gainetdinov RR (March 2011). "The physiology, signaling, and pharmacology of dopamine receptors". Pharmacological Reviews. 63 (1): 182–217. doi:10.1124/pr.110.002642. PMID 21303898.
- ↑ Universal protein resource accession number P14416 for "D(2) dopamine receptor" at UniProt.
- ↑ Salmas RE, Yurtsever M, Stein M, Durdagi S (May 2015). "Modeling and protein engineering studies of active and inactive states of human dopamine D2 receptor (D2R) and investigation of drug/receptor interactions". Molecular Diversity. 19 (2): 321–32. doi:10.1007/s11030-015-9569-3. PMID 25652238.
- ↑ Seeman P, Chau-Wong M, Tedesco J, Wong K (November 1975). "Brain receptors for antipsychotic drugs and dopamine: direct binding assays". Proceedings of the National Academy of Sciences of the United States of America. 72 (11): 4376–80. doi:10.1073/pnas.72.11.4376. PMID 1060115.
- ↑ Armstrong D, Strange PG (June 2001). "Dopamine D2 receptor dimer formation: evidence from ligand binding". The Journal of Biological Chemistry. 276 (25): 22621–9. doi:10.1074/jbc.M006936200. PMID 11278324.
- ↑ Guo W, Shi L, Javitch JA (February 2003). "The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer". The Journal of Biological Chemistry. 278 (7): 4385–8. doi:10.1074/jbc.C200679200. PMID 12496294.
- ↑ Durdagi S, Salmas RE, Stein M, Yurtsever M, Seeman P (February 2016). "Binding Interactions of Dopamine and Apomorphine in D2High and D2Low States of Human Dopamine D2 Receptor Using Computational and Experimental Techniques". ACS Chemical Neuroscience. 7 (2): 185–95. doi:10.1021/acschemneuro.5b00271. PMID 26645629.
- ↑ Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV (February 2003). "Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor". Human Molecular Genetics. 12 (3): 205–16. doi:10.1093/hmg/ddg055. PMID 12554675.
- ↑ Arinami T, Gao M, Hamaguchi H, Toru M (April 1997). "A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia". Human Molecular Genetics. 6 (4): 577–82. doi:10.1093/hmg/6.4.577. PMID 9097961.
- ↑ Glatt SJ, Faraone SV, Tsuang MT (July 2004). "DRD2 -141C insertion/deletion polymorphism is not associated with schizophrenia: results of a meta-analysis". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 128B (1): 21–3. doi:10.1002/ajmg.b.30007. PMID 15211624.
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- ↑ Wang J, Zhao C, Chen B, Liu ZL (January 2004). "Polymorphisms of dopamine receptor and transporter genes and hallucinations in Parkinson's disease". Neuroscience Letters. 355 (3): 193–6. doi:10.1016/j.neulet.2003.11.006. PMID 14732464.
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- ↑ 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.
- ↑ 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 Sciences. 63 (3): 215–22. doi:10.1016/S0024-3205(98)00262-8. PMID 9698051.
- ↑ Wang GJ, Volkow ND, Thanos PK, Fowler JS (2004). "Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review". Journal of Addictive Diseases. 23 (3): 39–53. doi:10.1300/J069v23n03_04. PMID 15256343.
- ↑ Huang R, Griffin SA, Taylor M, Vangveravong S, Mach RH, Dillon GH, Luedtke RR (2013). "The effect of SV 293, a D2 dopamine receptor-selective antagonist, on D2 receptor-mediated GIRK channel activation and adenylyl cyclase inhibition". Pharmacology. 92 (1–2): 84–9. doi:10.1159/000351971. PMID 23942137.
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- ↑ 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". Molecular Pharmacology. 62 (3): 507–13. doi:10.1124/mol.62.3.507. PMID 12181426.
- ↑ 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". The Journal of Biological Chemistry. 274 (28): 19894–900. doi:10.1074/jbc.274.28.19894. PMID 10391935.
- ↑ Kabbani N, Negyessy L, Lin R, Goldman-Rakic P, Levenson R (October 2002). "Interaction with neuronal calcium sensor NCS-1 mediates desensitization of the D2 dopamine receptor". The Journal of Neuroscience. 22 (19): 8476–86. PMID 12351722.
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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 ... 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)
- ↑ Harmeier A, Obermueller S, Meyer CA, Revel FG, Buchy D, Chaboz S, Dernick G, Wettstein JG, Iglesias A, Rolink A, Bettler B, Hoener MC (November 2015). "Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers". European Neuropsychopharmacology. 25 (11): 2049–61. doi:10.1016/j.euroneuro.2015.08.011. PMID 26372541.
Interaction of TAAR1 with D2R altered the subcellular localization of TAAR1 and increased D2R agonist binding affinity.
- ↑ Maggio R, Millan MJ (February 2010). "Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance". Current Opinion in Pharmacology. 10 (1): 100–7. doi:10.1016/j.coph.2009.10.001. PMID 19896900.
- ↑ Hasbi A, O'Dowd BF, George SR (February 2010). "Heteromerization of dopamine D2 receptors with dopamine D1 or D5 receptors generates intracellular calcium signaling by different mechanisms". Current Opinion in Pharmacology. 10 (1): 93–9. doi:10.1016/j.coph.2009.09.011. PMC 2818238. PMID 19897420.
- ↑ Albizu L, Holloway T, González-Maeso J, Sealfon SC (September 2011). "Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors". Neuropharmacology. 61 (4): 770–7. doi:10.1016/j.neuropharm.2011.05.023. PMC 3556730. PMID 21645528.
- Receptors,+Dopamine+D2 at the US National Library of Medicine Medical Subject Headings (MeSH)
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.