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 [1] The dopamine D2 receptor is the main receptor for all antipsychotic drugs. Any drug that does not interfere with dopamine action at the D2 receptor does not have an antipsychotic action.
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.[2]
In mice, regulation of D2R surface expression by the calcium sensor NCS-1 in the dentate gyrus is involved in exploration, synaptic plasticity and memory formation.[3]
In flies, activation of the D2 autoreceptor protected dopamine neurons from cell death induced by a toxin mimicking Parkinson's disease pathology.[4]
Isoforms
Alternative splicing of this gene results in three transcript variants encoding different isoforms.[5]
The long form (D2Lh) has the "canonical" sequence and functions as a classic post-synaptic receptor.[6] The short form (D2Sh) is pre-synaptic and functions as an autoreceptor that regulates the levels of dopamine in the synaptic cleft.[6] Agonism of D2sh receptors inhibits dopamine release; antagonism increases dopaminergic release.[6] A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ.[7]
Genetics
Allelic variants:
- A-241G
- C132T, G423A, T765C, C939T, C957T, and G1101A[8]
- Cys311Ser
- -141C insertion/deletion[9] The polymorphisms have been investigated with respect to association with schizophrenia.[10]
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.[11] DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motorfluctuations but not hallucinations in Parkinson's disease.[12][13]
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)[14]
- Brexpiprazole/OPC-34712
- Cariprazine
- RP5063
- GSK-789,472 – Also D3 antagonist, with good selectivity over other receptors [15]
- Ketamine (also NMDA antagonist)
- LSD – in vitro, LSD was found to be a partial agonist and potentiates dopamine-mediated prolactin secretion in lactotrophs.[16] LSD is also a 5-HT2A agonist.
- Modafinil
- Roxindole (only at the D2 autoreceptors)
- OSU-6162 – Also 5-HT2A 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[17]
- Typical antipsychotics
- SV 293[18]
- Yohimbine
- D2sh selective (presynaptic autoreceptors)
- Amisulpride (low doses)
- UH-232
Allosteric modulators
Functionally selective ligands
- See reference[24]
Protein-protein interactions
The dopamine receptor D2 has been shown to interact with EPB41L1,[25] PPP1R9B[26] and NCS-1.[27]
Receptor oligomers
The D2 receptor forms receptor heterodimers in vivo (in living animals) with other G protein-coupled receptors; these include:[28]
The D2 receptor has been shown to form hetorodimers in vitro (and possibly in vivo) with DRD3,[31] DRD5,[32] and 5-HT2A.[33]
See also
- Dopamine receptor
Notes
References
External links
- 醫學主題詞表（MeSH）：Receptors,+Dopamine+D2
- Pappas, Stephanie. Study: Genes Influence Who Your Friends Are. Imaginova Corp. LiveScience. [20 January 2011].
User:Panintelize/沙盒3引用了美国国家医学图书馆提供的資料，这些資料属于公共领域。
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Template:Dopaminergics