Dopamine receptor D2

Last updated

DRD2
7jvr Dopamine receptor D2.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases DRD2 , D2DR, D2R, dopamine receptor D2
External IDs OMIM: 126450; MGI: 94924; HomoloGene: 22561; GeneCards: DRD2; OMA:DRD2 - orthologs
Orthologs
SpeciesHumanMouse
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
View/Edit Human View/Edit Mouse

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]

Contents

Function

D2 receptors are coupled to Gi 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 (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. [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:

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

Partial agonists

Antagonists

D2sh selective (presynaptic autoreceptors)

Allosteric modulators

Heterobivalent ligands

Dual D2AR/ A2AAR ligands

Functionally selective ligands

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]

The D2 receptor has been shown to form heterodimers in vitro (and possibly in vivo) with DRD3, [56] DRD5, [57] and 5-HT2A. [58]

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. [54] [55]

Related Research Articles

<span class="mw-page-title-main">Dopamine receptor</span> Class of G protein-coupled receptors

Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein interactions. The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.

<span class="mw-page-title-main">Dopamine antagonist</span> Drug which blocks dopamine receptors

A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and as such they have found use in treating schizophrenia, bipolar disorder, and stimulant psychosis. Several other dopamine antagonists are antiemetics used in the treatment of nausea and vomiting.

Dopamine receptor D<sub>4</sub> Protein-coding gene in the species Homo sapiens

The dopamine receptor D4 is a dopamine D2-like G protein-coupled receptor encoded by the DRD4 gene on chromosome 11 at 11p15.5.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">Pramipexole</span> Dopamine agonist medication

Pramipexole, sold under the brand Mirapex among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipexole is a dopamine agonist of the non-ergoline class.

<span class="mw-page-title-main">Dopamine agonist</span> Compound that activates dopamine receptors

A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors. Dopamine agonists are primarily used in the treatment of the motor symptoms of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome. They are also used off-label in the treatment of clinical depression. Impulse control disorders are associated with the use of dopamine agonists for whatever condition.

<span class="mw-page-title-main">SB-277,011-A</span> Chemical compound

SB-277,011A is a drug which acts as a potent and selective dopamine D3 receptor antagonist, which is around 80–100 times selective for D3 over D2, and lacks any partial agonist activity.

Dopamine receptor D<sub>1</sub> Protein-coding gene in humans

Dopamine receptor D1, also known as DRD1. It is one of the two types of D1-like receptor family — receptors D1 and D5. It is a protein that in humans is encoded by the DRD1 gene.

5-HT<sub>1A</sub> receptor Serotonin receptor protein distributed in the cerebrum and raphe nucleus

The serotonin 1A receptor is a subtype of serotonin receptors, or 5-HT receptors, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarization and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.

Dopamine receptor D<sub>3</sub> Subtype of Dopamine Receptor

Dopamine receptor D3 is a protein that in humans is encoded by the DRD3 gene.

<span class="mw-page-title-main">TAAR1</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene. TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells, astrocytes, and in the intracellular milieu within the presynaptic plasma membrane of monoamine neurons in the central nervous system (CNS). TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al. TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms.

<span class="mw-page-title-main">Sultopride</span> Antipsychotic medication

Sultopride (trade names Barnetil, Barnotil, Topral) is an atypical antipsychotic of the benzamide chemical class used in Europe, Japan, and Hong Kong for the treatment of schizophrenia. It was launched by Sanofi-Aventis in 1976. Sultopride acts as a selective D2 and D3 receptor antagonist. It has also been shown to have clinically relevant affinity for the GHB receptor as well, a property it shares in common with amisulpride and sulpiride.

<span class="mw-page-title-main">UH-232</span> Chemical compound

UH-232 ((+)-UH232) is a drug which acts as a subtype selective mixed agonist-antagonist for dopamine receptors, acting as a weak partial agonist at the D3 subtype, and an antagonist at D2Sh autoreceptors on dopaminergic nerve terminals. It causes dopamine release in the brain and has a stimulant effect, as well as blocking the behavioural effects of cocaine. It may also serve as a 5-HT2A receptor agonist, based on animal studies. It was investigated in clinical trials for the treatment of schizophrenia, but unexpectedly caused symptoms to become worse.

<span class="mw-page-title-main">S-15535</span> Chemical compound

S-15535 is a phenylpiperazine drug which is a potent and highly selective 5-HT1A receptor ligand that acts as an agonist and antagonist at the presynaptic and postsynaptic 5-HT1A receptors, respectively. It has anxiolytic properties.

<span class="mw-page-title-main">7-OH-DPAT</span> Dopamine receptor agonist compound

7-OH-DPAT is a synthetic compound that acts as a dopamine receptor agonist with reasonable selectivity for the D3 receptor subtype, and low affinity for serotonin receptors, unlike its structural isomer 8-OH-DPAT. 7-OH-DPAT is self-administered in several animal models, and is used to study its addiction effects to cocaine.

<span class="mw-page-title-main">Roxindole</span> Dopaminergic & serotonergic drug developed for schizophrenia treatment

Roxindole (EMD-49,980) is a dopaminergic and serotonergic drug which was originally developed by Merck KGaA for the treatment of schizophrenia. In clinical trials its antipsychotic efficacy was only modest but it was unexpectedly found to produce potent and rapid antidepressant and anxiolytic effects. As a result, roxindole was further researched for the treatment of depression instead. It has also been investigated as a therapy for Parkinson's disease and prolactinoma.

<span class="mw-page-title-main">PNU-99,194</span> Chemical compound

PNU-99,194(A) (or U-99,194(A)) is a drug which acts as a moderately selective D3 receptor antagonist with ~15-30-fold preference for D3 over the D2 subtype. Though it has substantially greater preference for D3 over D2, the latter receptor does still play some role in its effects, as evidenced by the fact that PNU-99,194 weakly stimulates both prolactin secretion and striatal dopamine synthesis, actions it does not share with the more selective (100-fold) D3 receptor antagonists S-14,297 and GR-103,691.

<span class="mw-page-title-main">Cariprazine</span> Atypical antipsychotic medicine

Cariprazine, sold under the brand name Vraylar among others, is an atypical antipsychotic developed by Gedeon Richter, which is used in the treatment of schizophrenia, bipolar mania, bipolar depression, and major depressive disorder. It acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors, with high selectivity for the D3 receptor. It is taken by mouth. The most prevalent side effects include nausea, mild sedation, fatigue, and dizziness. At higher dosages, there is an increased risk for restlessness, insomnia, and tremors.

<span class="mw-page-title-main">L-741,626</span> Chemical compound

L-741,626 is a drug which acts as a potent and selective antagonist for the dopamine receptor D2. It has good selectivity over the related D3 and D4 subtypes and other receptors. L-741,626 is used for laboratory research into brain function and has proved particularly useful for distinguishing D2 mediated responses from those produced by the closely related D3 subtype, and for studying the roles of these subtypes in the action of cocaine and amphetamines in the brain.

<span class="mw-page-title-main">Clorotepine</span> Antipsychotic medication

Clorotepine, also known as octoclothepin or octoclothepine, is an antipsychotic of the tricyclic group which was derived from perathiepin in 1965 and marketed in the Czech Republic by Spofa in or around 1971 for the treatment of schizophrenic psychosis.

References

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