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. 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.

# Function
This gene encodes the D2 subtype of the dopamine receptor, which is coupled to Gi subtype of G protein-coupled receptor. 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. A recent study has shown a potential role for D2R in retrieval of fear memories in the prelimbic cortex.
In flies, activation of the D2 autoreceptor protected dopamine neurons from cell death induced by MPP+, a toxin mimicking Parkinson's disease pathology.

# Isoforms
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 (D2HighR) and inactive (D2LowR) 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 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.

# 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. 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
- 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.

# 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 2adrenergic 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 2adrenoceptor 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.
- Brexpiprazole
- Cariprazine
- GSK-789,472  Also D3 antagonist, with good selectivity over other receptors 
- 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. LSD is also a 5-HT2A agonist.
- OSU-6162  also 5-HT2A partial agonist, acts as "dopamine stabilizer"
- Roxindole (only at the D2 autoreceptors)
- RP5063
- Salvinorin A  also -opioid agonist.

## 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
- Typical antipsychotics
- SV 293
- Yohimbine
- Buspirone D2 presynaptic autoreceptors (low dose) and postsynaptic D2 receptors (at higher doses) antagonist
- Amisulpride (low doses)
- UH-232

## Allosteric modulators
- Homocysteine  negative allosteric modulator
- PAOPA
- SB-269,652 

## 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)

## Functionally selective ligands
- UNC9994

# Proteinprotein 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:
- D1D2 dopamine receptor heteromer
- D2adenosine A2A
- D2ghrelin receptor
- D2shTAAR1
The D2 receptor has been shown to form hetorodimers in vitro (and possibly in vivo) with DRD3, DRD5, and 5-HT2A.