Dopamine receptor D2

Dopamine receptor D₂, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene.The dopamine D₂ receptor was discovered in 1975 by Philip Seeman who had named it as the antipsychotic dopamine receptor The dopamine D₂ receptor is the main receptor for all antipsychotic drugs.

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.

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.

In flies, activation of the D₂ autoreceptor protected dopamine neurons from cell death induced by 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.

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 (Caberl)
• 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 (Abilify in the US)
• Brexpiprazole/OPC-34712
• Cariprazine
• RP5063
• GSK-789,472 – Also D₃ antagonist, with good selectivity over other receptors
• Ketamine (also NMDA antagonist)
• 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.
• Modafinil
• Roxindole (only at the D₂ autoreceptors)
• OSU-6162 – Also 5-HT_2A partial agonist, acts as "dopamine stabilizer"
• Salvinorin A – Also κ-opioid agonist.

Antagonists

• Atypical antipsychotics
• Desmethoxyfallypride
• Domperidone – D₂ and D₃ antagonist; does not cross the blood-brain barrier
• 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

D₂sh selective (presynaptic autoreceptors)

• Amisulpride (low doses)
• UH-232

Allosteric modulators

• Homocysteine – negative allosteric modulator
• PAOPA
• SB-269,652

Functionally selective ligands

• See reference

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 (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.

External links

• Receptors, Dopamine D2 at the US National Library of Medicine Medical Subject Headings (MeSH)

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