Dopamine receptor D2

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Lua error in Module:Infobox_gene at line 33: attempt to index field 'wikibase' (a nil value). 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.

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 neuronal calcium sensor-1 (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:

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 motor fluctuations 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

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Partial agonists

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Antagonists

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D2sh selective (presynaptic autoreceptors)

Allosteric modulators

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Functionally selective ligands

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]

Notes

  1. D2sh–TAAR1 is a presynaptic heterodimer which involves the relocation of TAAR1 from the intracellular space to D2sh at the plasma membrane, increased D2sh agonist binding affinity, and signal transduction through the calcium–PKCNFAT pathway and G-protein independent PKBGSK3 pathway.[29][30]

References

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  7. UniProt P14416
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External links

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