D2 Receptor

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

D₂ receptors are coupled to G_i 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

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 (D₂^''High''R) and inactive (D₂^''Low''R) 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 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
* 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-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

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
* 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)
* UH-232

Allosteric modulators

* Homocysteine – negative allosteric modulator
* PAOPA
* SB-269,652
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 Nicotinic acetylcholine receptor, nAChR antagonist)

Dual D₂AR/ A_2AAR ligands

* Dual agonists for A_2AAR 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 A_2A
*D₂– ghrelin receptor
* D_2sh–TAAR1

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

See also

* Prolactin modulator

Explanatory notes

References

External links

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{{Dopaminergics

Dopamine receptors
Biology of attention deficit hyperactivity disorder
Psychopharmacology