Dopamine receptor D2

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; OMA:DRD2 - orthologs
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 49,251,927 bp [2] End 49,319,477 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in putamen nucleus accumbens testicle Pituitary Gland caudate nucleus anterior pituitary triceps brachii muscle pars compacta pars reticulata ventral tegmental area Top expressed in superior frontal gyrus striatum of neuraxis dorsal striatum nucleus accumbens olfactory epithelium lumbar subsegment of spinal cord neural layer of retina olfactory tubercle embryo ankle joint More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein homodimerization activity potassium channel regulator activity dopamine neurotransmitter receptor activity, coupled via Gi/Go identical protein binding dopamine neurotransmitter receptor activity G protein-coupled receptor activity protein binding signal transducer activity adrenergic receptor activity dopamine binding signaling receptor binding ionotropic glutamate receptor binding protein heterodimerization activity Cellular component cytoplasmic vesicle sperm flagellum endocytic vesicle acrosomal vesicle dendritic spine synaptic vesicle membrane perikaryon plasma membrane dendrite ciliary membrane axon terminus integral component of membrane postsynaptic density membrane lateral plasma membrane axon intracellular anatomical structure 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 population 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 response to inactivity phospholipase C-activating dopamine receptor signaling pathway modulation of chemical synaptic transmission grooming behavior 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 signaling pathway response to axon injury striatum development synaptic transmission, dopaminergic nervous 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 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 by RNA polymerase II 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 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: 49.25 – 49.32 Mb PubMed search [3] [4]
Wikidata
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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 H. 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]}

Function

D₂ receptors are coupled to G_i subtype of G protein. 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 and inactive 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, ^[20] autism ^{[ citation needed ]} and Parkinson's disease.^{[ citation needed ]} 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.^{[ citation needed ]} In most cases, it was observed that the problems regarding the D₂R states may have genetic roots and are controlled by drug therapies.^{[ citation needed ]} 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. ^[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]}

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]} 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. ^[31]

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 ^[32]
• Armodafinil – although primarily thought to be a weak DAT inhibitor, armodafinil is also a D₂ partial agonist. ^[33]
• Modafinil - The (R)-(−)-enantiomer, known as Armodafinil in its pure form ^[33]
• Brexpiprazole
• Cariprazine
• Cannabidiol
• GSK-789,472 – Also D₃ antagonist, with good selectivity over other receptors ^[34]
• Ketamine (also NMDA antagonist)
• LSD – in vitro, LSD was found to be a partial agonist and potentiates dopamine-mediated prolactin secretion in lactotrophs. ^[35] 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)
• Brilaroxazine(RP5063)
• Salvinorin A – also κ-opioid agonist.
• Memantine – Also NMDA antagonist ^{[36] [37]}

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 ^[38]
• Typical antipsychotics
• SV 293 ^[39]
• Yohimbine
• Buspirone  – D₂ presynaptic autoreceptors (low dose) and postsynaptic D₂ receptors (at higher doses) antagonist ^[40]

D₂sh selective (presynaptic autoreceptors)

• Amisulpride (low doses)
• UH-232
• Sulpiride

Allosteric modulators

• Homocysteine – negative allosteric modulator ^[41]
• PAOPA ^[42]
• SB269652 ^{[43] [44] [45] [46]}

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) ^[47]

Dual D₂AR/ A_2AAR ligands

• Dual agonists for A_2AAR and D2AR receptors have been developed. ^[48]

Functionally selective ligands

• UNC9994 ^[49]

Protein–protein interactions

The dopamine receptor D₂ has been shown to interact with EPB41L1, ^[50] PPP1R9B ^[51] and NCS-1. ^[52]

Receptor oligomers

The D₂ receptor forms receptor heterodimers in vivo (i.e., in living animals) with other G protein-coupled receptors; these include: ^[53]

• 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 heterodimers in vitro (and possibly in vivo) with DRD₃, ^[56] DRD₅, ^[57] and 5-HT_2A. ^[58]

See also

• Prolactin modulator

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. ^{[54] [55]}

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External links

• Receptors,+Dopamine+D2 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Pappas S (17 January 2011). "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.