Dopamine receptor D2
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene.The dopamine D2 receptor was discovered in 1975 by Philip Seeman who had named it as the antipsychotic dopamine receptor [1] The dopamine D2 receptor is the main receptor for all antipsychotic drugs. Any drug that does not interfere with dopamine action at the D2 receptor does not have an antipsychotic action.
Function
[编辑]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.[2]
In mice, regulation of D2R surface expression by the calcium sensor NCS-1 in the dentate gyrus is involved in exploration, synaptic plasticity and memory formation.[3]
In flies, activation of the D2 autoreceptor protected dopamine neurons from cell death induced by a toxin mimicking Parkinson's disease pathology.[4]
Isoforms
[编辑]Alternative splicing of this gene results in three transcript variants encoding different isoforms.[5]
The long form (D2Lh) has the "canonical" sequence and functions as a classic post-synaptic receptor.[6] The short form (D2Sh) is pre-synaptic and functions as an autoreceptor that regulates the levels of dopamine in the synaptic cleft.[6] Agonism of D2sh receptors inhibits dopamine release; antagonism increases dopaminergic release.[6] A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ.[7]
Genetics
[编辑]Allelic variants:
- A-241G
- C132T, G423A, T765C, C939T, C957T, and G1101A[8]
- Cys311Ser
- -141C insertion/deletion[9] The polymorphisms have been investigated with respect to association with schizophrenia.[10]
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.[11] DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor fluctuations but not hallucinations in Parkinson's disease.[12][13]
Ligands
[编辑]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
[编辑]- Bromocriptine – full agonist
- Cabergoline (Caberl)
- 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.
Partial agonists
[编辑]- Aplindore
- Aripiprazole (Abilify in the US)[14]
- Brexpiprazole/OPC-34712
- Cariprazine
- RP5063
- GSK-789,472 – Also D3 antagonist, with good selectivity over other receptors [15]
- Ketamine (also NMDA antagonist)
- LSD – in vitro, LSD was found to be a partial agonist and potentiates dopamine-mediated prolactin secretion in lactotrophs.[16] LSD is also a 5-HT2A agonist.
- Modafinil
- Roxindole (only at the D2 autoreceptors)
- OSU-6162 – Also 5-HT2A partial agonist, acts as "dopamine stabilizer"
- Salvinorin A – Also κ-opioid agonist.
Antagonists
[编辑]- Atypical antipsychotics
- Desmethoxyfallypride
- Domperidone – D2 and D3 antagonist; does not cross the blood-brain barrier
- Eticlopride
- Fallypride
- Hydroxyzine (Vistaril, Atarax)
- Itopride
- L-741,626 – highly selective D2 antagonist
- C11 Raclopride radiolabled – commonly employed in positron emission tomography studies[17]
- Typical antipsychotics
- SV 293[18]
- Yohimbine
- D2sh selective (presynaptic autoreceptors)
- Amisulpride (low doses)
- UH-232
Allosteric modulators
[编辑]- Homocysteine – negative allosteric modulator[19]
- PAOPA[20]
- SB-269,652 [21][22][23]
Functionally selective ligands
[编辑]- See reference[24]
Protein-protein interactions
[编辑]The dopamine receptor D2 has been shown to interact with EPB41L1,[25] PPP1R9B[26] and NCS-1.[27]
Receptor oligomers
[编辑]The D2 receptor forms receptor heterodimers in vivo (in living animals) with other G protein-coupled receptors; these include:[28]
The D2 receptor has been shown to form hetorodimers in vitro (and possibly in vivo) with DRD3,[31] DRD5,[32] and 5-HT2A.[33]
See also
[编辑]Notes
[编辑]- ^ 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.[29][30]
References
[编辑]- ^ Madras BK. 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. 2013, 22 (1): 62–78. PMID 23323533. doi:10.1080/0964704X.2012.678199.
- ^ Usiello A, Baik JH, Rougé-Pont F, Picetti R, Dierich A, LeMeur M, Piazza PV, Borrelli E. Distinct functions of the two isoforms of dopamine D2 receptors. Nature. Nov 2000, 408 (6809): 199–203. PMID 11089973. doi:10.1038/35041572.
- ^ Saab BJ, Georgiou J, Nath A, Lee FJ, Wang M, Michalon A, Liu F, Mansuy IM, Roder JC. NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory. Neuron. Sep 2009, 63 (5): 643–56. PMID 19755107. doi:10.1016/j.neuron.2009.08.014.
- ^ Wiemerslage L, Schultz BJ, Ganguly A, Lee D. Selective degeneration of dopaminergic neurons by MPP(+) and its rescue by D2 autoreceptors in Drosophila primary culture. Journal of Neurochemistry. Aug 2013, 126 (4): 529–40. PMID 23452092. doi:10.1111/jnc.12228.
- ^ Entrez Gene: DRD2 dopamine receptor D2.
- ^ 6.0 6.1 6.2 Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacological Reviews. Mar 2011, 63 (1): 182–217. PMID 21303898. doi:10.1124/pr.110.002642.
- ^ UniProt P14416
- ^ Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV. Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Human Molecular Genetics. Feb 2003, 12 (3): 205–16. PMID 12554675. doi:10.1093/hmg/ddg055.
- ^ Arinami T, Gao M, Hamaguchi H, Toru M. A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Human Molecular Genetics. Apr 1997, 6 (4): 577–82. PMID 9097961. doi:10.1093/hmg/6.4.577.
- ^ Glatt SJ, Faraone SV, Tsuang MT. DRD2 -141C insertion/deletion polymorphism is not associated with schizophrenia: results of a meta-analysis. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. Jul 2004, 128B (1): 21–3. PMID 15211624. doi:10.1002/ajmg.b.30007.
- ^ Lucht M, Rosskopf D. Comment on "Genetically determined differences in learning from errors". Science. Jul 2008, 321 (5886): 200; author reply 200. PMID 18621654. doi:10.1126/science.1155372.
- ^ Wang J, Liu ZL, Chen B. Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD. Neurology. Jun 2001, 56 (12): 1757–9. PMID 11425949. doi:10.1212/WNL.56.12.1757.
- ^ Wang J, Zhao C, Chen B, Liu ZL. Polymorphisms of dopamine receptor and transporter genes and hallucinations in Parkinson's disease. Neuroscience Letters. Jan 2004, 355 (3): 193–6. PMID 14732464. doi:10.1016/j.neulet.2003.11.006.
- ^ Clinical Pharmacology for Abilify. RxList.com. 2010-01-21 [2010-01-21].
- ^ 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. The identification of a selective dopamine D2 partial agonist, D3 antagonist displaying high levels of brain exposure. Bioorganic & Medicinal Chemistry Letters. Mar 2010, 20 (6): 2013–6. PMID 20153647. doi:10.1016/j.bmcl.2010.01.090.
- ^ Giacomelli S, Palmery M, Romanelli L, Cheng CY, Silvestrini B. 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. 1998, 63 (3): 215–22. PMID 9698051. doi:10.1016/S0024-3205(98)00262-8.
- ^ Wang GJ, Volkow ND, Thanos PK, Fowler JS. Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review. Journal of Addictive Diseases. 2004, 23 (3): 39–53. PMID 15256343. doi:10.1300/J069v23n03_04.
- ^ Huang R, Griffin SA, Taylor M, Vangveravong S, Mach RH, Dillon GH, Luedtke RR. The effect of SV 293, a D2 dopamine receptor-selective antagonist, on D2 receptor-mediated GIRK channel activation and adenylyl cyclase inhibition. Pharmacology. 2013, 92 (1–2): 84–9. PMID 23942137. doi:10.1159/000351971.
- ^ Agnati LF, Ferré S, Genedani S, Leo G, Guidolin D, Filaferro M, Carriba P, Casadó V, Lluis C, Franco R, Woods AS, Fuxe K. Allosteric modulation of dopamine D2 receptors by homocysteine. Journal of Proteome Research. Nov 2006, 5 (11): 3077–83. PMID 17081059. doi:10.1021/pr0601382.
- ^ Beyaert MG, Daya RP, Dyck BA, Johnson RL, Mishra RK. PAOPA, a potent dopamine D2 receptor allosteric modulator, prevents and reverses behavioral and biochemical abnormalities in an amphetamine–sensitized preclinical animal model of schizophrenia. European Neuropsychopharmacology. Mar 2013, 23 (3): 253–62. PMID 22658400. doi:10.1016/j.euroneuro.2012.04.010.
- ^ 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. A new mechanism of allostery in a G protein–coupled receptor dimer. Nature Chemical Biology. Sep 2014, 10 (9): 745–52. PMID 25108820. doi:10.1038/nchembio.1593.
- ^ Maggio R, Scarselli M, Capannolo M, Millan MJ. Novel dimensions of D3 receptor function: Focus on heterodimerisation, transactivation and allosteric modulation. European Neuropsychopharmacology. Sep 2015, 25 (9): 1470–9. PMID 25453482. doi:10.1016/j.euroneuro.2014.09.016.
- ^ 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. The tetrahydroisoquinoline derivative SB269,652 is an allosteric antagonist at dopamine D3 and D2 receptors. Molecular Pharmacology. Nov 2010, 78 (5): 925–34. PMC 2981362
. PMID 20702763. doi:10.1124/mol.110.065755.
- ^ Möller D, Kling RC, Skultety M, Leuner K, Hübner H, Gmeiner P. Functionally selective dopamine D₂, D₃ receptor partial agonists. Journal of Medicinal Chemistry. Jun 2014, 57 (11): 4861–75. PMID 24831693. doi:10.1021/jm5004039.
- ^ Binda AV, Kabbani N, Lin R, Levenson R. D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1N. Molecular Pharmacology. Sep 2002, 62 (3): 507–13. PMID 12181426. doi:10.1124/mol.62.3.507.
- ^ Smith FD, Oxford GS, Milgram SL. Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting protein. The Journal of Biological Chemistry. Jul 1999, 274 (28): 19894–900. PMID 10391935. doi:10.1074/jbc.274.28.19894.
- ^ Kabbani N, Negyessy L, Lin R, Goldman-Rakic P, Levenson R. Interaction with neuronal calcium sensor NCS-1 mediates desensitization of the D2 dopamine receptor. The Journal of Neuroscience. Oct 2002, 22 (19): 8476–86. PMID 12351722.
- ^ Beaulieu JM, Espinoza S, Gainetdinov RR. Dopamine receptors - IUPHAR Review 13. British Journal of Pharmacology. Jan 2015, 172 (1): 1–23. PMC 4280963 . PMID 25671228. doi:10.1111/bph.12906.
- ^ Grandy DK, Miller GM, Li JX. "TAARgeting Addiction"-The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference. Drug Alcohol Depend. February 2016, 159: 9–16. PMID 26644139. doi:10.1016/j.drugalcdep.2015.11.014.
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. Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers. Eur Neuropsychopharmacol. 2015, 25 (11): 2049–61. PMID 26372541. doi:10.1016/j.euroneuro.2015.08.011.
Interaction of TAAR1 with D2R altered the subcellular localization of TAAR1 and increased D2R agonist binding affinity.
- ^ Maggio R, Millan MJ. Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance. Current Opinion in Pharmacology. Feb 2010, 10 (1): 100–7. PMID 19896900. doi:10.1016/j.coph.2009.10.001.
- ^ Hasbi A, O'Dowd BF, George SR. Heteromerization of dopamine D2 receptors with dopamine D1 or D5 receptors generates intracellular calcium signaling by different mechanisms. Current Opinion in Pharmacology. Feb 2010, 10 (1): 93–9. PMC 2818238 . PMID 19897420. doi:10.1016/j.coph.2009.09.011.
- ^ Albizu L, Holloway T, González-Maeso J, Sealfon SC. Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors. Neuropharmacology. Sep 2011, 61 (4): 770–7. PMC 3556730 . PMID 21645528. doi:10.1016/j.neuropharm.2011.05.023.
External links
[编辑]- 醫學主題詞表（MeSH）：Receptors,+Dopamine+D2
- Pappas, Stephanie. Study: Genes Influence Who Your Friends Are. Imaginova Corp. LiveScience. [20 January 2011].