Dopamine receptor D2

Function

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

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

While optimal dopamine levels favor D1R cognitive stabilization, it is the D2R that mediates the cognitive flexibility in humans.

Isoforms{{anchor|D2sh}}

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 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.

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 assist in the management of these conditions, 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.

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.

Genetics

Allelic variants:

• A-241G
• C132T, G423A, T765C, C939T, C957T, and G1101A
• Cys311Ser
• -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. 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.

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

• 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.

Partial agonists

• Aplindore
• Aripiprazole
• Armodafinil – although primarily thought to be a weak DAT inhibitor, armodafinil is also a D2 partial agonist.
• Modafinil - The (R)-(−)-enantiomer, known as Armodafinil in its pure form
• Brexpiprazole
• Cariprazine
• Cannabidiol
• GSK-789,472 – Also D3 antagonist, with good selectivity over other receptors
• Ketamine (also NMDA antagonist)
• 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)
• Brilaroxazine(RP5063)
• Salvinorin A – also κ-opioid agonist.
• Memantine – Also NMDA antagonist

Antagonists

• 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
• L-741,626 – 4-phenylpiperidine (such as haloperidol), highly selective D2 inverse agonist
• ST-148 (D2L antagonist) - D2L selective antagonist
• 11C-radiolabeled Raclopride – commonly employed in positron emission tomography studies
• Typical antipsychotics
• SV 293
• Yohimbine
• Buspirone D2 presynaptic autoreceptors (low dose) and postsynaptic D2 receptors (at higher doses) antagonist

;D2sh selective (presynaptic autoreceptors)

• Amisulpride (low doses)
• CGP-25454A
• Sulpiride
• UH-232

Allosteric modulators

• Homocysteine – negative allosteric modulator
• PAOPA
• SB269652

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)

Dual D₂AR/ A_2AAR ligands

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

Functionally selective ligands

• UNC9994

Protein–protein interactions

The dopamine receptor D2 has been shown to interact with EPB41L1, PPP1R9B and NCS-1.

Receptor oligomers

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

• D1–D2 dopamine receptor heteromer
• D2–adenosine A2A
• D2–ghrelin receptor
• D2sh–TAAR1

The D2 receptor has been shown to form heterodimers in vitro (and possibly in vivo) with DRD3, DRD5, and 5-HT2A.

Explanatory notes

References

References

1. (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.
2. (March 2018). "Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone". Nature.
3. (29 January 2018). "NIMH » Molecular Secrets Revealed: Antipsychotic Docked in its Receptor".
4. (November 2000). "Distinct functions of the two isoforms of dopamine D2 receptors". Nature.
5. (September 2009). "NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory". Neuron.
6. (November 2017). "Investigating the role of dopamine receptor- and parvalbumin-expressing cells in extinction of conditioned fear". Neurobiology of Learning and Memory.
7. (March 2020). "Dopamine D2 receptors in discrimination learning and spine enlargement". Nature.
8. (August 2013). "Selective degeneration of dopaminergic neurons by MPP(+) and its rescue by D2 autoreceptors in Drosophila primary culture". Journal of Neurochemistry.
9. (April 2018). "Effects of tolcapone and bromocriptine on cognitive stability and flexibility". Psychopharmacology.
10. (February 2018). "Interactions of Motivation and Cognitive Control". Current Opinion in Behavioral Sciences.
11. (2018). "Superior cognitive goal maintenance in carriers of genetic markers linked to reduced striatal D2 receptor density (C957T and DRD2/ANKK1-TaqIA)". PLOS ONE.
12. "Entrez Gene: DRD2 dopamine receptor D2".
13. (March 2011). "The physiology, signaling, and pharmacology of dopamine receptors". Pharmacological Reviews.
14. {{UniProt Full. P14416. D(2) dopamine receptor
15. (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.
16. (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.
17. (February 2018). "2 receptor". Biochemical Pharmacology.
18. (June 2001). "Dopamine D2 receptor dimer formation: evidence from ligand binding". The Journal of Biological Chemistry.
19. (February 2003). "The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer". The Journal of Biological Chemistry.
20. (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.
21. (February 2003). "Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor". Human Molecular Genetics.
22. (April 1997). "A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia". Human Molecular Genetics.
23. (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.
24. (July 2008). "Comment on "Genetically determined differences in learning from errors"". Science.
25. (June 2001). "Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD". Neurology.
26. (January 2004). "Polymorphisms of dopamine receptor and transporter genes and hallucinations in Parkinson's disease". Neuroscience Letters.
27. (2020). "The effect of rs1076560 (DRD2) and rs4680 (COMT) on tardive dyskinesia and cognition in schizophrenia subjects". Psychiatric Genetics.
28. (2010-01-21). "Clinical Pharmacology for Abilify". RxList.com.
29. (August 2009). "Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil". Synapse.
30. (March 2010). "The identification of a selective dopamine D2 partial agonist, D3 antagonist displaying high levels of brain exposure". Bioorganic & Medicinal Chemistry Letters.
31. (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.
32. (February 2008). "Memantine agonist action at dopamine D2High receptors". Synapse.
33. (August 2012). "The role of memantine in the treatment of psychiatric disorders other than the dementias: a review of current preclinical and clinical evidence". CNS Drugs.
34. (2004). "Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review". Journal of Addictive Diseases.
35. (2013). "The effect of SV 293, a D2 dopamine receptor-selective antagonist, on D2 receptor-mediated GIRK channel activation and adenylyl cyclase inhibition". Pharmacology.
36. (1998). "Effects of buspirone on plasma neurotransmitters in healthy subjects". Journal of Neural Transmission.
37. (November 2006). "Allosteric modulation of dopamine D2 receptors by homocysteine". Journal of Proteome Research.
38. (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.
39. (September 2014). "A new mechanism of allostery in a G protein-coupled receptor dimer". Nature Chemical Biology.
40. (September 2015). "Novel dimensions of D3 receptor function: Focus on heterodimerisation, transactivation and allosteric modulation". European Neuropsychopharmacology.
41. (November 2010). "The tetrahydroisoquinoline derivative SB269,652 is an allosteric antagonist at dopamine D3 and D2 receptors". Molecular Pharmacology.
42. (June 2017). "3 Receptors, SB269652 May Lead to a New Generation of Antipsychotic Drugs". Molecular Pharmacology.
43. (August 2015). "Bifunctional compounds targeting both D2 and non-α7 nACh receptors: design, synthesis and pharmacological characterization". European Journal of Medicinal Chemistry.
44. (August 2021). "Structure-Guided Design of G-Protein-Coupled Receptor Polypharmacology". Angewandte Chemie.
45. (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.
46. (September 2002). "D2 and D3 dopamine receptor cell surface localization mediated by interaction with protein 4.1N". Molecular Pharmacology.
47. (July 1999). "Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting protein". The Journal of Biological Chemistry.
48. (October 2002). "Interaction with neuronal calcium sensor NCS-1 mediates desensitization of the D2 dopamine receptor". The Journal of Neuroscience.
49. (January 2015). "Dopamine receptors – IUPHAR Review 13". British Journal of Pharmacology.
50. (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.
51. (November 2015). "Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers". European Neuropsychopharmacology.
52. (February 2010). "Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance". Current Opinion in Pharmacology.
53. (February 2010). "Heteromerization of dopamine D2 receptors with dopamine D1 or D5 receptors generates intracellular calcium signaling by different mechanisms". Current Opinion in Pharmacology.
54. (September 2011). "Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors". Neuropharmacology.