Dopamine receptor D2

Dopamine receptor D2, also known as D2R, is a is_associated_with::protein that, in humans, is encoded by the DRD2 is_associated_with::gene.

Function
This gene encodes the D2 subtype of the is_associated_with::dopamine receptor, which is coupled to Gi subtype of is_associated_with::G protein-coupled receptor. This is_associated_with::G protein-coupled receptor inhibits is_associated_with::adenylyl cyclase activity.

In mice, regulation of D2R surface expression by the calcium sensor NCS-1 in the is_associated_with::dentate gyrus is involved in exploration, is_associated_with::synaptic plasticity and memory formation.

In flies, activation of the D2 is_associated_with::autoreceptor protected dopamine neurons from cell death induced by a toxin mimicking is_associated_with::Parkinson's disease pathology.

Isoforms
is_associated_with::Alternative splicing of this gene results in three transcript variants encoding different is_associated_with::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 is_associated_with::autoreceptor and regulates the levels of dopamine in the synaptic cleft. Agonism of D2sh receptors inhibits dopamine release; antagonism increases is_associated_with::dopaminergic release. A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ.

Genetics
Allelic variants:
 * is_associated_with::A-241G
 * is_associated_with::C132T, is_associated_with::G423A, is_associated_with::T765C, is_associated_with::C939T, is_associated_with::C957T, and is_associated_with::G1101A
 * is_associated_with::Cys311Ser
 * -141C insertion/deletion The polymorphisms have been investigated with respect to association with is_associated_with::schizophrenia.

Some researchers have previously associated the polymorphism Taq 1A (is_associated_with::rs1800497) to the DRD2 gene. However, the polymorphism resides in is_associated_with::exon 8 of the is_associated_with::ANKK1 gene. DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor fluctuations in Parkinson's disease.

Ligands
Most of the older is_associated_with::antipsychotic drugs such as is_associated_with::chlorpromazine and is_associated_with::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 is_associated_with::serotonin and is_associated_with::histamine, resulting in a range of side-effects and making them poor agents for scientific research. In similar manner, older dopamine agonists used for is_associated_with::Parkinson's disease such as is_associated_with::bromocriptine and is_associated_with::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

 * is_associated_with::N,N-Propyldihydrexidine - analogue of the D1/D5 agonist is_associated_with::dihydrexidine; Selective for postsynaptic D2 receptor over the presynaptic D2 is_associated_with::autoreceptor.
 * is_associated_with::Cabergoline (Caberl)
 * is_associated_with::Talipexole - selective for D2 over other dopamine receptors, but also acts as α2-adrenoceptor agonist and 5-HT3 antagonist.
 * is_associated_with::Piribedil - also D3 receptor agonist and α2-adrenergic antagonist
 * is_associated_with::Pramipexole - also D3, D4 receptor agonist
 * is_associated_with::Quinpirole - also D3 receptor agonist
 * is_associated_with::Quinelorane - affinity for D2 > D3
 * is_associated_with::Bromocriptine - full agonist
 * is_associated_with::Ropinirole - full agonist
 * is_associated_with::Sumanirole - full agonist; highly selective

Partial agonists

 * is_associated_with::Aplindore
 * is_associated_with::Aripiprazole (Abilify in USA)
 * is_associated_with::Brexpiprazole/is_associated_with::OPC-34712


 * is_associated_with::Cariprazine
 * is_associated_with::RP5063
 * is_associated_with::GSK-789,472 - Also D3 antagonist, with good selectivity over other receptors
 * is_associated_with::Ketamine (also NMDA antagonist)
 * is_associated_with::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.
 * is_associated_with::Roxindole (only at the D2 autoreceptors)
 * is_associated_with::OSU-6162 - Also 5-HT2A partial agonist, acts as "dopamine stabilizer"
 * is_associated_with::Salvinorin A - Also κ-opioid agonist.

Antagonists

 * is_associated_with::Atypical antipsychotics
 * is_associated_with::Domperidone - D2 and D3 antagonist; does not cross the blood-brain barrier
 * is_associated_with::Eticlopride
 * is_associated_with::Fallypride
 * is_associated_with::Desmethoxyfallypride
 * is_associated_with::L-741,626 (3-[4-(4-Chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole) - highly selective D2 antagonist
 * is_associated_with::Raclopride - Radiolabled C11 Raclopride is commonly employed in is_associated_with::Positron emission tomography studies
 * is_associated_with::Hydroxyzine (Vistaril, Atarax)
 * is_associated_with::Itopride
 * SV 293
 * is_associated_with::Typical antipsychotics
 * is_associated_with::Yohimbine


 * D2Sh selective (presynaptic autoreceptors)
 * is_associated_with::Amisulpride (low doses)
 * is_associated_with::UH-232

Allosteric modulators

 * is_associated_with::Homocysteine - allosteric antagonist
 * is_associated_with::PAOPA
 * SB-269,652

Functionally selective ligands

 * See reference

Protein-protein interactions
The dopamine receptor D2 has been shown to interact with is_associated_with::EPB41L1, is_associated_with::PPP1R9B and is_associated_with::NCS-1.

Receptor oligomers
The D2 receptor forms heteromers with the following receptors: dopamine D1 (→ D1-D2), D3, D5, 5-HT2A, adenosine A2A, CB1, mGlu5.