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.[1] 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.[2][3]

Function

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.[4]

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.[5] A recent study has shown a potential role for D2R in retrieval of fear memories in the prelimbic cortex.[6]

In flies, activation of the D2 autoreceptor protected dopamine neurons from cell death induced by MPP+, a toxin mimicking Parkinson's disease pathology.[7]

Isoforms

Alternative splicing of this gene results in three transcript variants encoding different isoforms.[8]

The long form (D2Lh) has the "canonical" sequence and functions as a classic post-synaptic receptor.[9] The short form (D2Sh) is pre-synaptic and functions as an autoreceptor that regulates the levels of dopamine in the synaptic cleft.[9] Agonism of D2sh receptors inhibits dopamine release; antagonism increases dopaminergic release.[9] A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ.[10]

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.[11]

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.[12] 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.[13] 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.[14][15] 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.

Genetics

Allelic variants:

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.[19] DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor fluctuations but not hallucinations in Parkinson's disease.[20][21]

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

Partial agonists

Antagonists

D2sh selective (presynaptic autoreceptors)

Allosteric modulators

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)[34]

Functionally selective ligands

Protein–protein interactions

The dopamine receptor D2 has been shown to interact with EPB41L1,[36] PPP1R9B[37] and NCS-1.[38]

Receptor oligomers

The D2 receptor forms receptor heterodimers in vivo (i.e., in living animals) with other G protein-coupled receptors; these include:[39]

The D2 receptor has been shown to form hetorodimers in vitro (and possibly in vivo) with DRD3,[42] DRD5,[43] and 5-HT2A.[44]

See also

Notes

  1. ↑ 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.[40][41]

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ "NIMH » Molecular Secrets Revealed: Antipsychotic Docked in its Receptor". www.nimh.nih.gov. Retrieved 2018-11-26.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ "Entrez Gene: DRD2 dopamine receptor D2".
  9. ↑ 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.
  10. ↑ Universal protein resource accession number P14416 for "D(2) dopamine receptor" at UniProt.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ Lucht M, Rosskopf D (July 2008). "Comment on "Genetically determined differences in learning from errors"". Science. 321 (5886): 200, author reply 200. doi:10.1126/science.1155372. PMID 18621654.
  20. ↑ Wang J, Liu ZL, Chen B (June 2001). "Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD". Neurology. 56 (12): 1757–9. doi:10.1212/WNL.56.12.1757. PMID 11425949.
  21. ↑ 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.
  22. ↑ "Clinical Pharmacology for Abilify". RxList.com. 2010-01-21. Retrieved 2010-01-21.
  23. ↑ Seeman P, Guan HC, Hirbec H (August 2009). "Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil". Synapse. 63 (8): 698–704. doi:10.1002/syn.20647. PMID 19391150.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ Lechin F, van der Dijs B, Jara H, Orozco B, Baez S, Benaim M, Lechin M, Lechin A (1998). "Effects of buspirone on plasma neurotransmitters in healthy subjects". Journal of Neural Transmission. 105 (6–7): 561–73. doi:10.1007/s007020050079. PMID 9826102.
  29. ↑ Agnati LF, Ferré S, Genedani S, Leo G, Guidolin D, Filaferro M, Carriba P, Casadó V, Lluis C, Franco R, Woods AS, Fuxe K (November 2006). "Allosteric modulation of dopamine D2 receptors by homocysteine". Journal of Proteome Research. 5 (11): 3077–83. doi:10.1021/pr0601382. PMID 17081059.
  30. ↑ Beyaert MG, Daya RP, Dyck BA, Johnson RL, Mishra RK (March 2013). "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. 23 (3): 253–62. doi:10.1016/j.euroneuro.2012.04.010. PMID 22658400.
  31. ↑ 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 (September 2014). "A new mechanism of allostery in a G protein-coupled receptor dimer". Nature Chemical Biology. 10 (9): 745–52. doi:10.1038/nchembio.1593. PMC 4138267. PMID 25108820.
  32. ↑ Maggio R, Scarselli M, Capannolo M, Millan MJ (September 2015). "Novel dimensions of D3 receptor function: Focus on heterodimerisation, transactivation and allosteric modulation". European Neuropsychopharmacology. 25 (9): 1470–9. doi:10.1016/j.euroneuro.2014.09.016. PMID 25453482.
  33. ↑ 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 (November 2010). "The tetrahydroisoquinoline derivative SB269,652 is an allosteric antagonist at dopamine D3 and D2 receptors". Molecular Pharmacology. 78 (5): 925–34. doi:10.1124/mol.110.065755. PMC 2981362. PMID 20702763.
  34. ↑ Matera C, Pucci L, Fiorentini C, Fucile S, Missale C, Grazioso G, Clementi F, Zoli M, De Amici M, Gotti C, Dallanoce C (August 2015). "Bifunctional compounds targeting both D2 and non-α7 nACh receptors: design, synthesis and pharmacological characterization". European Journal of Medicinal Chemistry. 101: 367–83. doi:10.1016/j.ejmech.2015.06.039. PMID 26164842.
  35. ↑ 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 (November 2011). "Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy". Proceedings of the National Academy of Sciences of the United States of America. 108 (45): 18488–93. doi:10.1073/pnas.1104807108. PMC 3215024. PMID 22025698.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ Beaulieu JM, Espinoza S, Gainetdinov RR (January 2015). "Dopamine receptors - IUPHAR Review 13". British Journal of Pharmacology. 172 (1): 1–23. doi:10.1111/bph.12906. PMC 4280963. PMID 25671228.
  40. ↑ Grandy DK, Miller GM, Li JX (February 2016). ""TAARgeting Addiction"--The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug and Alcohol Dependence. 159: 9–16. doi:10.1016/j.drugalcdep.2015.11.014. PMC 4724540. PMID 26644139. 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)
  41. ↑ 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.
  42. ↑ 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.
  43. ↑ 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.
  44. ↑ 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.

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