Biology:Dopamine receptor D2

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Short description: Main receptor for most antipsychotic drugs


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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

D2 receptors are coupled to Gi subtype of G protein. 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] Studies have shown potential roles for D2R in retrieval of fear memories in the prelimbic cortex[6] and in discrimination learning in the nucleus accumbens.[7]

In flies, activation of the D2 autoreceptor protected dopamine neurons from cell death induced by MPP+, a toxin mimicking Parkinson's disease pathology.[8]

While optimal dopamine levels favor D1R cognitive stabilization, it is the D2R that mediates the cognitive flexibility in humans.[9][10][11]

Isoforms

Alternative splicing of this gene results in three transcript variants encoding different isoforms.[12]

The long form (D2Lh) has the "canonical" sequence and functions as a classic post-synaptic receptor.[13] The short form (D2Sh) is pre-synaptic and functions as an autoreceptor that regulates the levels of dopamine in the synaptic cleft.[13] Agonism of D2sh receptors inhibits dopamine release; antagonism increases dopaminergic release.[13] A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ.[14]

Active and inactive 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.[15]

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.[16] 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 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.[17]

Oligomerization of D2R

It was observed that D2R exists in dimeric forms or higher order oligomers.[18] 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.[19][20]

Genetics

Allelic variants:

  • A-241G
  • C132T, G423A, T765C, C939T, C957T, and G1101A[21]
  • Cys311Ser
  • -141C insertion/deletion[22] The polymorphisms have been investigated with respect to association with schizophrenia.[23]

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.[24] DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor fluctuations but not hallucinations in Parkinson's disease.[25][26] 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.[27]

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)[43]

Dual D2AR/ A2AAR ligands

  • Dual agonists for A2AAR and D2AR receptors have been developed.[44]

Functionally selective ligands

Protein–protein interactions

The dopamine receptor D2 has been shown to interact with EPB41L1,[46] PPP1R9B[47] and NCS-1.[48]

Receptor oligomers

The D2 receptor forms receptor heterodimers in vivo (i.e., in living animals) with other G protein-coupled receptors; these include:[49]

The D2 receptor has been shown to form hetorodimers in vitro (and possibly in vivo) with DRD3,[52] DRD5,[53] and 5-HT2A.[54]

See also

Explanatory 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.[50][51]

References

  1. ↑ "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. 2013. doi:10.1080/0964704X.2012.678199. PMID 23323533. 
  2. ↑ "Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone". Nature 555 (7695): 269–273. March 2018. doi:10.1038/nature25758. PMID 29466326. Bibcode: 2018Natur.555..269W. 
  3. ↑ "NIMH » Molecular Secrets Revealed: Antipsychotic Docked in its Receptor" (in en). https://www.nimh.nih.gov/news/science-news/2018/molecular-secrets-revealed-antipsychotic-docked-in-its-receptor.shtml. 
  4. ↑ "Distinct functions of the two isoforms of dopamine D2 receptors". Nature 408 (6809): 199–203. November 2000. doi:10.1038/35041572. PMID 11089973. Bibcode: 2000Natur.408..199U. 
  5. ↑ "NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory". Neuron 63 (5): 643–56. September 2009. doi:10.1016/j.neuron.2009.08.014. PMID 19755107. 
  6. ↑ "Investigating the role of dopamine receptor- and parvalbumin-expressing cells in extinction of conditioned fear". Neurobiology of Learning and Memory 145: 7–17. November 2017. doi:10.1016/j.nlm.2017.08.009. PMID 28842281. 
  7. ↑ "Dopamine D2 receptors in discrimination learning and spine enlargement". Nature 579 (7800): 555–560. March 2020. doi:10.1038/s41586-020-2115-1. PMID 32214250. Bibcode: 2020Natur.579..555I. https://www.nature.com/articles/s41586-020-2115-1. 
  8. ↑ "Selective degeneration of dopaminergic neurons by MPP(+) and its rescue by D2 autoreceptors in Drosophila primary culture". Journal of Neurochemistry 126 (4): 529–40. August 2013. doi:10.1111/jnc.12228. PMID 23452092. 
  9. ↑ "Effects of tolcapone and bromocriptine on cognitive stability and flexibility". Psychopharmacology 235 (4): 1295–1305. April 2018. doi:10.1007/s00213-018-4845-4. PMID 29427081. 
  10. ↑ "Interactions of Motivation and Cognitive Control". Current Opinion in Behavioral Sciences 19: 83–90. February 2018. doi:10.1016/j.cobeha.2017.11.009. PMID 30035206. 
  11. ↑ "Superior cognitive goal maintenance in carriers of genetic markers linked to reduced striatal D2 receptor density (C957T and DRD2/ANKK1-TaqIA)". PLOS ONE 13 (8): e0201837. 2018. doi:10.1371/journal.pone.0201837. PMID 30125286. Bibcode: 2018PLoSO..1301837P. 
  12. ↑ "Entrez Gene: DRD2 dopamine receptor D2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1813. 
  13. ↑ 13.0 13.1 13.2 "The physiology, signaling, and pharmacology of dopamine receptors". Pharmacological Reviews 63 (1): 182–217. March 2011. doi:10.1124/pr.110.002642. PMID 21303898. 
  14. ↑ Universal protein resource accession number P14416 for "D(2) dopamine receptor" at UniProt.
  15. ↑ "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. May 2015. doi:10.1007/s11030-015-9569-3. PMID 25652238. 
  16. ↑ "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. November 1975. doi:10.1073/pnas.72.11.4376. PMID 1060115. Bibcode: 1975PNAS...72.4376S. 
  17. ↑ "2 receptor". Biochemical Pharmacology 148: 315–328. February 2018. doi:10.1016/j.bcp.2018.01.002. PMID 29325769. 
  18. ↑ "Dopamine D2 receptor dimer formation: evidence from ligand binding". The Journal of Biological Chemistry 276 (25): 22621–9. June 2001. doi:10.1074/jbc.M006936200. PMID 11278324. 
  19. ↑ "The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer". The Journal of Biological Chemistry 278 (7): 4385–8. February 2003. doi:10.1074/jbc.C200679200. PMID 12496294. 
  20. ↑ "Binding Interactions of Dopamine and Apomorphine in D2High and D2Low States of Human Dopamine D2 Receptor Using Computational and Experimental Techniques" (in EN). ACS Chemical Neuroscience 7 (2): 185–95. February 2016. doi:10.1021/acschemneuro.5b00271. PMID 26645629. 
  21. ↑ "Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor". Human Molecular Genetics 12 (3): 205–16. February 2003. doi:10.1093/hmg/ddg055. PMID 12554675. 
  22. ↑ "A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia". Human Molecular Genetics 6 (4): 577–82. April 1997. doi:10.1093/hmg/6.4.577. PMID 9097961. 
  23. ↑ "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. July 2004. doi:10.1002/ajmg.b.30007. PMID 15211624. 
  24. ↑ "Comment on "Genetically determined differences in learning from errors"". Science 321 (5886): 200; author reply 200. July 2008. doi:10.1126/science.1155372. PMID 18621654. Bibcode: 2008Sci...321..200L. 
  25. ↑ "Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD". Neurology 56 (12): 1757–9. June 2001. doi:10.1212/WNL.56.12.1757. PMID 11425949. 
  26. ↑ "Polymorphisms of dopamine receptor and transporter genes and hallucinations in Parkinson's disease". Neuroscience Letters 355 (3): 193–6. January 2004. doi:10.1016/j.neulet.2003.11.006. PMID 14732464. 
  27. ↑ "The effect of rs1076560 (DRD2) and rs4680 (COMT) on tardive dyskinesia and cognition in schizophrenia subjects". Psychiatric Genetics 30 (5): 125–135. 2020. doi:10.1097/YPG.0000000000000258. PMID 32931693. 
  28. ↑ "Clinical Pharmacology for Abilify". RxList.com. 2010-01-21. http://www.rxlist.com/abilify-drug.htm. 
  29. ↑ 29.0 29.1 "Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil". Synapse 63 (8): 698–704. August 2009. doi:10.1002/syn.20647. PMID 19391150. 
  30. ↑ "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. March 2010. doi:10.1016/j.bmcl.2010.01.090. PMID 20153647. 
  31. ↑ "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. 1998. doi:10.1016/S0024-3205(98)00262-8. PMID 9698051. 
  32. ↑ "Memantine agonist action at dopamine D2High receptors". Synapse 62 (2): 149–53. February 2008. doi:10.1002/syn.20472. PMID 18000814. 
  33. ↑ "The role of memantine in the treatment of psychiatric disorders other than the dementias: a review of current preclinical and clinical evidence". CNS Drugs 26 (8): 663–90. August 2012. doi:10.2165/11634390-000000000-00000. PMID 22784018. 
  34. ↑ "Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review". Journal of Addictive Diseases 23 (3): 39–53. 2004. doi:10.1300/J069v23n03_04. PMID 15256343. 
  35. ↑ "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. 2013. doi:10.1159/000351971. PMID 23942137. 
  36. ↑ "Effects of buspirone on plasma neurotransmitters in healthy subjects". Journal of Neural Transmission 105 (6–7): 561–73. 1998. doi:10.1007/s007020050079. PMID 9826102. 
  37. ↑ "Allosteric modulation of dopamine D2 receptors by homocysteine". Journal of Proteome Research 5 (11): 3077–83. November 2006. doi:10.1021/pr0601382. PMID 17081059. 
  38. ↑ "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. March 2013. doi:10.1016/j.euroneuro.2012.04.010. PMID 22658400. 
  39. ↑ "A new mechanism of allostery in a G protein-coupled receptor dimer". Nature Chemical Biology 10 (9): 745–52. September 2014. doi:10.1038/nchembio.1593. PMID 25108820. 
  40. ↑ "Novel dimensions of D3 receptor function: Focus on heterodimerisation, transactivation and allosteric modulation". European Neuropsychopharmacology 25 (9): 1470–9. September 2015. doi:10.1016/j.euroneuro.2014.09.016. PMID 25453482. 
  41. ↑ "The tetrahydroisoquinoline derivative SB269,652 is an allosteric antagonist at dopamine D3 and D2 receptors". Molecular Pharmacology 78 (5): 925–34. November 2010. doi:10.1124/mol.110.065755. PMID 20702763. 
  42. ↑ "3 Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs". Molecular Pharmacology 91 (6): 586–594. June 2017. doi:10.1124/mol.116.107607. PMID 28265019. 
  43. ↑ "Bifunctional compounds targeting both D2 and non-α7 nACh receptors: design, synthesis and pharmacological characterization". European Journal of Medicinal Chemistry 101: 367–83. August 2015. doi:10.1016/j.ejmech.2015.06.039. PMID 26164842. 
  44. ↑ "Structure-Guided Design of G-Protein-Coupled Receptor Polypharmacology". Angewandte Chemie 60 (33): 18022–18030. August 2021. doi:10.1002/anie.202101478. PMID 33904641. 
  45. ↑ "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. November 2011. doi:10.1073/pnas.1104807108. PMID 22025698. Bibcode: 2011PNAS..10818488A. 
  46. ↑ "D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1N". Molecular Pharmacology 62 (3): 507–13. September 2002. doi:10.1124/mol.62.3.507. PMID 12181426. 
  47. ↑ "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. July 1999. doi:10.1074/jbc.274.28.19894. PMID 10391935. 
  48. ↑ "Interaction with neuronal calcium sensor NCS-1 mediates desensitization of the D2 dopamine receptor". The Journal of Neuroscience 22 (19): 8476–86. October 2002. doi:10.1523/JNEUROSCI.22-19-08476.2002. PMID 12351722. 
  49. ↑ "Dopamine receptors – IUPHAR Review 13". British Journal of Pharmacology 172 (1): 1–23. January 2015. doi:10.1111/bph.12906. PMID 25671228. 
  50. ↑ ""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. February 2016. doi:10.1016/j.drugalcdep.2015.11.014. 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)". 
  51. ↑ "Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers". European Neuropsychopharmacology 25 (11): 2049–61. November 2015. 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.". 
  52. ↑ "Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance". Current Opinion in Pharmacology 10 (1): 100–7. February 2010. doi:10.1016/j.coph.2009.10.001. PMID 19896900. 
  53. ↑ "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. February 2010. doi:10.1016/j.coph.2009.09.011. PMID 19897420. 
  54. ↑ "Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors". Neuropharmacology 61 (4): 770–7. September 2011. doi:10.1016/j.neuropharm.2011.05.023. PMID 21645528. 

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