Dopamine receptor D2
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.[4] The dopamine D2 receptor is the main receptor for all antipsychotic drugs.
Contents
Function[edit]
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.[5]
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.[6]
In flies, activation of the D2 autoreceptor protected dopamine neurons from cell death induced by a toxin mimicking Parkinson's disease pathology.[7]
Isoforms[edit]
Alternative splicing of this gene results in three transcript variants encoding different isoforms.[8]
The long form (D2Lh) has the "canonical" sequence and functions as a classic post-synaptic receptor.[9] The short form (D2Sh) is pre-synaptic and functions as an autoreceptor that regulates the levels of dopamine in the synaptic cleft.[9] Agonism of D2sh receptors inhibits dopamine release; antagonism increases dopaminergic release.[9] A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ.[10]
Genetics[edit]
Allelic variants:
- A-241G
- C132T, G423A, T765C, C939T, C957T, and G1101A[11]
- Cys311Ser
- -141C insertion/deletion[12] The polymorphisms have been investigated with respect to association with schizophrenia.[13]
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.[14] DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor fluctuations but not hallucinations in Parkinson's disease.[15][16]
Ligands[edit]
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[edit]
- 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[edit]
- Aplindore
- Aripiprazole[17]
- Armodafinil – although primarily thought to be a weak DAT inhibitor, armodafinil is also a D2 partial agonist.[18]
- Brexpiprazole
- Cariprazine
- GSK-789,472 – Also D3 antagonist, with good selectivity over other receptors [19]
- 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.[20] LSD is also a 5-HT2A agonist.
- OSU-6162 – also 5-HT2A partial agonist, acts as "dopamine stabilizer"
- Roxindole (only at the D2 autoreceptors)
- RP5063
- Salvinorin A – also κ-opioid agonist.
Antagonists[edit]
- Atypical antipsychotics (except aripiprazole, brexpiprazole, and any other D2 receptor partial agonists)
- 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[21]
- Typical antipsychotics
- SV 293[22]
- Yohimbine
- D2sh selective (presynaptic autoreceptors)
- Amisulpride (low doses)
- UH-232
Allosteric modulators[edit]
- Homocysteine – negative allosteric modulator[23]
- PAOPA[24]
- SB-269,652 [25][26][27]
Functionally selective ligands[edit]
- See reference[28]
Protein–protein interactions[edit]
The dopamine receptor D2 has been shown to interact with EPB41L1,[29] PPP1R9B[30] and NCS-1.[31]
Receptor oligomers[edit]
The D2 receptor forms receptor heterodimers in vivo (in living animals) with other G protein-coupled receptors; these include:[32]
The D2 receptor has been shown to form hetorodimers in vitro (and possibly in vivo) with DRD3,[35] DRD5,[36] and 5-HT2A.[37]
Notes[edit]
- ^ 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–PKC–NFAT pathway and G-protein independent PKB–GSK3 pathway.[33][34]
References[edit]
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- ^ Saab BJ, Georgiou J, Nath A, Lee FJ, Wang M, Michalon A, Liu F, Mansuy IM, Roder JC (Sep 2009). "NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory". Neuron. 63 (5): 643–56. doi:10.1016/j.neuron.2009.08.014. PMID 19755107.
- ^ Wiemerslage L, Schultz BJ, Ganguly A, Lee D (Aug 2013). "Selective degeneration of dopaminergic neurons by MPP(+) and its rescue by D2 autoreceptors in Drosophila primary culture". Journal of Neurochemistry. 126 (4): 529–40. doi:10.1111/jnc.12228. PMID 23452092.
- ^ "Entrez Gene: DRD2 dopamine receptor D2".
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- ^ Universal protein resource accession number P14416 for "D(2) dopamine receptor" at UniProt.
- ^ Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV (Feb 2003). "Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor". Human Molecular Genetics. 12 (3): 205–16. doi:10.1093/hmg/ddg055. PMID 12554675.
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- ^ Glatt SJ, Faraone SV, Tsuang MT (Jul 2004). "DRD2 -141C insertion/deletion polymorphism is not associated with schizophrenia: results of a meta-analysis". American Journal of Medical Genetics Part B. 128B (1): 21–3. doi:10.1002/ajmg.b.30007. PMID 15211624.
- ^ Lucht M, Rosskopf D (Jul 2008). "Comment on "Genetically determined differences in learning from errors"". Science. 321 (5886): 200; author reply 200. doi:10.1126/science.1155372. PMID 18621654.
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- ^ Giacomelli S, Palmery M, Romanelli L, Cheng CY, Silvestrini B (1998). "Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro". Life Sciences. 63 (3): 215–22. doi:10.1016/S0024-3205(98)00262-8. PMID 9698051.
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This original observation of TAAR1 and DA D2R interaction has subsequently been confirmed and expanded upon with observations that both receptors can heterodimerize with each other under certain conditions ... Additional DA D2R/TAAR1 interactions with functional consequences are revealed by the results of experiments demonstrating that in addition to the cAMP/PKA pathway (Panas et al., 2012) stimulation of TAAR1-mediated signaling is linked to activation of the Ca++/PKC/NFAT pathway (Panas et al.,2012) and the DA D2R-coupled, G protein-independent AKT/GSK3 signaling pathway (Espinoza et al., 2015; Harmeier et al., 2015), such that concurrent TAAR1 and DA DR2R activation could result in diminished signaling in one pathway (e.g. cAMP/PKA) but retention of signaling through another (e.g., Ca++/PKC/NFA)
- ^ Harmeier A, Obermueller S, Meyer CA, Revel FG, Buchy D, Chaboz S, Dernick G, Wettstein JG, Iglesias A, Rolink A, Bettler B, Hoener MC (2015). "Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers". Eur Neuropsychopharmacol. 25 (11): 2049–61. doi:10.1016/j.euroneuro.2015.08.011. PMID 26372541.
Interaction of TAAR1 with D2R altered the subcellular localization of TAAR1 and increased D2R agonist binding affinity.
- ^ Maggio R, Millan MJ (Feb 2010). "Dopamine D2-D3 receptor heteromers: pharmacological properties and therapeutic significance". Current Opinion in Pharmacology. 10 (1): 100–7. doi:10.1016/j.coph.2009.10.001. PMID 19896900.
- ^ Hasbi A, O'Dowd BF, George SR (Feb 2010). "Heteromerization of dopamine D2 receptors with dopamine D1 or D5 receptors generates intracellular calcium signaling by different mechanisms". Current Opinion in Pharmacology. 10 (1): 93–9. doi:10.1016/j.coph.2009.09.011. PMC 2818238
. PMID 19897420.
- ^ Albizu L, Holloway T, González-Maeso J, Sealfon SC (Sep 2011). "Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors". Neuropharmacology. 61 (4): 770–7. doi:10.1016/j.neuropharm.2011.05.023. PMC 3556730
. PMID 21645528.
External links[edit]
- Receptors, Dopamine D2 at the US National Library of Medicine Medical Subject Headings (MeSH)
- Pappas, Stephanie. "Study: Genes Influence Who Your Friends Are". Imaginova Corp. LiveScience. Retrieved 20 January 2011.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.