Dopamine receptor D₂

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.[5] 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.[6][7]

DRD2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 6CM4
Identifiers
Aliases	DRD2, D2DR, D2R, dopamine receptor D2
External IDs	OMIM: 126450 MGI: 94924 HomoloGene: 22561 GeneCards: DRD2
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11q23.2 Start 113,409,605 bp[1] End 113,475,691 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 A5.3|9 26.72 cM Start 49,340,627 bp[2] End 49,408,177 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • protein homodimerization activity • drug binding • potassium channel regulator activity • dopamine neurotransmitter receptor activity, coupled via Gi/Go • identical protein binding • dopamine neurotransmitter receptor activity • G-protein coupled receptor activity • GO:0001948 protein binding • signal transducer activity • adrenergic receptor activity • dopamine binding • receptor binding • ionotropic glutamate receptor binding • protein heterodimerization activity Cellular component • cytoplasmic vesicle • sperm flagellum • endocytic vesicle • Acrosome • dendritic spine • synaptic vesicle membrane • perikaryon • cell membrane • dendrite • ciliary membrane • axon terminus • integral component of membrane • GO:0097483, GO:0097481 postsynaptic density • membrane • lateral plasma membrane • axon • intracellular • non-motile cilium • integral component of plasma membrane • dopaminergic synapse • glutamatergic synapse • GABA-ergic synapse • integral component of postsynaptic membrane • integral component of presynaptic membrane Biological process • negative regulation of cell proliferation • temperature homeostasis • adenylate cyclase-inhibiting dopamine receptor signaling pathway • adenohypophysis development • circadian regulation of gene expression • response to toxic substance • regulation of dopamine secretion • response to cocaine • response to amphetamine • sensory perception of smell • locomotory behavior • positive regulation of urine volume • response to ethanol • axonogenesis • positive regulation of glial cell-derived neurotrophic factor secretion • response to inactivity • phospholipase C-activating dopamine receptor signaling pathway • modulation of chemical synaptic transmission • personal grooming • negative regulation of protein kinase B signaling • associative learning • positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G-protein coupled signaling pathway • regulation of dopamine uptake involved in synaptic transmission • regulation of synaptic transmission, GABAergic • positive regulation of dopamine uptake involved in synaptic transmission • signal transduction • Wnt signaling pathway • adult walking behavior • branching morphogenesis of a nerve • negative regulation of cytosolic calcium ion concentration • negative regulation of innate immune response • regulation of phosphoprotein phosphatase activity • acid secretion • feeding behavior • positive regulation of G-protein coupled receptor protein signaling pathway • response to axon injury • striatum development • synaptic transmission, dopaminergic • neurological system process involved in regulation of systemic arterial blood pressure • peristalsis • regulation of long-term neuronal synaptic plasticity • activation of protein kinase activity • positive regulation of growth hormone secretion • regulation of sodium ion transport • forebrain development • response to light stimulus • orbitofrontal cortex development • prepulse inhibition • response to morphine • response to iron ion • positive regulation of ERK1 and ERK2 cascade • long-term memory • positive regulation of renal sodium excretion • negative regulation of insulin secretion • neuron-neuron synaptic transmission • GO:0007243 intracellular signal transduction • auditory behavior • behavioral response to ethanol • regulation of heart rate • adenylate cyclase-activating adrenergic receptor signaling pathway • positive regulation of cytokinesis • regulation of potassium ion transport • pigmentation • cellular calcium ion homeostasis • dopamine metabolic process • response to nicotine • regulation of MAPK cascade • response to histamine • negative regulation of synaptic transmission, glutamatergic • response to hypoxia • negative regulation of circadian sleep/wake cycle, sleep • negative regulation of protein secretion • synapse assembly • regulation of locomotion involved in locomotory behavior • dopamine receptor signaling pathway • negative regulation of dopamine receptor signaling pathway • startle response • positive regulation of receptor internalization • protein localization • arachidonic acid secretion • positive regulation of transcription from RNA polymerase II promoter • G-protein coupled receptor internalization • positive regulation of multicellular organism growth • positive regulation of long-term synaptic potentiation • negative regulation of dopamine secretion • adult behavior • cerebral cortex GABAergic interneuron migration • regulation of synapse structural plasticity • adenylate cyclase-modulating G-protein coupled receptor signaling pathway • response to drug • visual learning • negative regulation of cell migration • behavioral response to cocaine • positive regulation of neuroblast proliferation • negative regulation of blood pressure • release of sequestered calcium ion into cytosol • negative regulation of voltage-gated calcium channel activity • G-protein coupled receptor signaling pathway • negative regulation of adenylate cyclase activity • excitatory postsynaptic potential • negative regulation of protein phosphorylation • autophagy • positive regulation of neurogenesis • negative regulation of cell death • drinking behavior • adrenergic receptor signaling pathway • regulation of neurotransmitter uptake • postsynaptic modulation of chemical synaptic transmission • regulation of synaptic vesicle exocytosis Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1813	13489
Ensembl	ENSG00000149295	ENSMUSG00000032259
UniProt	P14416	P61168
RefSeq (mRNA)	NM_016574 NM_000795	NM_010077
RefSeq (protein)	NP_000786 NP_057658 NP_000786.1	NP_034207
Location (UCSC)	Chr 11: 113.41 – 113.48 Mb	Chr 9: 49.34 – 49.41 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

This gene encodes the D₂ subtype of the dopamine receptor, which is coupled to G_i subtype of G protein-coupled receptor. This G protein-coupled receptor inhibits adenylyl cyclase activity.[8]

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.[9] Studies have shown potential roles for D2R in retrieval of fear memories in the prelimbic cortex[10] and in discrimination learning in the nucleus accumbens.[11]

In flies, activation of the D₂ autoreceptor protected dopamine neurons from cell death induced by MPP+, a toxin mimicking Parkinson's disease pathology.[12]

While optimal dopamine levels favor D1R cognitive stabilization, it is the D2R that mediates the cognitive flexibility in humans.[13][14][15]

Isoforms

Alternative splicing of this gene results in three transcript variants encoding different isoforms.[16]

The long form (D2Lh) has the "canonical" sequence and functions as a classic post-synaptic receptor.[17] The short form (D2Sh) is pre-synaptic and functions as an autoreceptor that regulates the levels of dopamine in the synaptic cleft.[17] Agonism of D2sh receptors inhibits dopamine release; antagonism increases dopaminergic release.[17] A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ.[18]

Active (D₂^HighR) and inactive (D₂^LowR) forms

D2R conformers are equilibrated between two full active (D₂^HighR) and inactive (D₂^LowR) 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.[19]

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.[20] 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.

Allosteric pocket and orthosteric pocket

There are orthosteric binding site (OBS) and a secondary binding pocket (SBP) in dopamin 2 receptor, and interaction with the SBP is a requirement for allosteric pharmacology. The compound SB269652 is a negative allosteric modulator of the D2R.[21]

Oligomerization of D2R

It was observed that D2R exists in dimeric forms or higher order oligomers.[22] 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.[23][24] 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:

• A-241G
• C132T, G423A, T765C, C939T, C957T, and G1101A[25]
• Cys311Ser
• -141C insertion/deletion[26] The polymorphisms have been investigated with respect to association with schizophrenia.[27]

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.[28] DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor fluctuations but not hallucinations in Parkinson's disease.[29][30]

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
• 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[31]
• Armodafinil – although primarily thought to be a weak DAT inhibitor, armodafinil is also a D₂ partial agonist.[32]
• Modafinil - The (R)-(−)-enantiomer, known as Armodafinil in is pure form [32]
• Brexpiprazole
• Cariprazine
• GSK-789,472 – Also D₃ antagonist, with good selectivity over other receptors [33]
• 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.[34] LSD is also a 5-HT_2A agonist.
• OSU-6162 – also 5-HT_2A partial agonist, acts as "dopamine stabilizer"
• Roxindole (only at the D₂ autoreceptors)
• RP5063
• Salvinorin A – also κ-opioid agonist.
• Memantine – Also NMDA antagonist[35][36]

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
• Metoclopramide - Antiemetic - crosses Blood-brain Barrier - causes drug induced Parkinsonism.
• Eticlopride
• Fallypride
• Hydroxyzine (Vistaril, Atarax)
• Itopride
• L-741,626 – highly selective D₂ antagonist
• C¹¹ Raclopride radiolabled – commonly employed in positron emission tomography studies[37]
• Typical antipsychotics
• SV 293[38]
• Yohimbine
• Buspirone D₂ presynaptic autoreceptors (low dose) and postsynaptic D₂ receptors (at higher doses) antagonist[39]

D₂sh selective (presynaptic autoreceptors)

• Amisulpride (low doses)
• UH-232

Allosteric modulators

• Homocysteine – negative allosteric modulator[40]
• PAOPA[41]
• SB-269,652 [42][43][44]

SB-269,652[45]

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)[46]

Functionally selective ligands

• UNC9994[47]

Protein–protein interactions

The dopamine receptor D₂ has been shown to interact with EPB41L1,[48] PPP1R9B[49] and NCS-1.[50]

Receptor oligomers

The D₂ receptor forms receptor heterodimers in vivo (i.e., in living animals) with other G protein-coupled receptors; these include:[51]

• D₁–D₂ dopamine receptor heteromer
• D₂–adenosine A_2A
• D₂–ghrelin receptor
• D_2sh–TAAR1[note 1]

The D₂ receptor has been shown to form hetorodimers in vitro (and possibly in vivo) with DRD₃,[54] DRD₅,[55] and 5-HT_2A.[56]

See also

• Prolactin modulator

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.[52][53]

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External links

• Receptors,+Dopamine+D2 at the US National Library of Medicine Medical Subject Headings (MeSH)
• Pappas S. "Study: Genes Influence Who Your Friends Are". Imaginova Corp. LiveScience. Retrieved 20 January 2011.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.