Dopamine receptor D4

Dopamine receptor D4
Identifiers
Symbols	DRD4 ; D4DR
External IDs	OMIM: 126452 MGI: 94926 HomoloGene: 20215 IUPHAR: 217 ChEMBL: 219 GeneCards: DRD4 Gene
Gene ontology Molecular function • dopamine neurotransmitter receptor activity, coupled via Gi/Go • dopamine neurotransmitter receptor activity • protein binding • drug binding • G-protein coupled amine receptor activity • potassium channel regulator activity • SH3 domain binding • dopamine binding • identical protein binding Cellular component • plasma membrane • integral component of plasma membrane • cell cortex • vesicle membrane • membrane • neuronal cell body • terminal bouton • dendritic spine Biological process • activation of MAPK activity • behavioral fear response • synaptic transmission, dopaminergic • response to amphetamine • cellular calcium ion homeostasis • negative regulation of adenylate cyclase activity • adenylate cyclase-inhibiting dopamine receptor signaling pathway • dopamine receptor signaling pathway • synaptic transmission • sensory perception of chemical stimulus • short-term memory • circadian rhythm • adult locomotory behavior • olfactory learning • photoperiodism • positive regulation of adenylate cyclase activity involved in G-protein coupled receptor signaling pathway • negative regulation of cAMP biosynthetic process • positive regulation of sodium:proton antiporter activity • positive regulation of kinase activity • response to histamine • social behavior • regulation of dopamine metabolic process • dopamine metabolic process • fear response • regulation of circadian rhythm • regulation of neurotransmitter secretion • behavioral response to cocaine • behavioral response to ethanol • response to steroid hormone • arachidonic acid secretion • negative regulation of protein secretion • regulation of calcium-mediated signaling • positive regulation of dopamine uptake involved in synaptic transmission • retina development in camera-type eye • inhibitory postsynaptic potential • positive regulation of penile erection • negative regulation of voltage-gated calcium channel activity • positive regulation of excitatory postsynaptic potential Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1815	13491
Ensembl	ENSG00000069696	ENSMUSG00000025496
UniProt	P21917	P51436
RefSeq (mRNA)	NM_000797	NM_007878
RefSeq (protein)	NP_000788	NP_031904
Location (UCSC)	Chr 11: 0.64 – 0.64 Mb	Chr 7: 141.29 – 141.29 Mb
PubMed search

The dopamine receptor D₄ is a G protein-coupled receptor encoded by the DRD4 gene.^[1] As with other dopamine receptor subtypes, the D₄ receptor is activated by the neurotransmitter dopamine. It is linked to many neurological and psychiatric conditions^[2] including schizophrenia and bipolar disorder,^[3] addictive behaviors,^[4] Parkinsons disease,^[5] and eating disorders such as anorexia nervosa.^[6]

It is also a target for drugs which treat schizophrenia and Parkinson disease.^[7] The D₄ receptor is considered to be D₂-like in which the activated receptor inhibits the enzyme adenylate cyclase, thereby reducing the intracellular concentration of the second messenger cyclic AMP.^[8]

Genetics

The human protein is coded by the DRD4 on chromosome 11 located in 11p15.5.

There are slight variations (mutations/polymorphisms) in the human gene:

• A 48-base pair VNTR in exon 3
• C-521T in the promoter
• 13-base pair deletion of bases 235 to 247 in exon 1
• 12 base pair repeat in exon 1.^[9]
• Val194Gly
• A polymorphic tandem duplication of 120 bp

Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder,^[10] schizophrenia,^[11] and the personality trait of novelty seeking.^[12]

48-base pair VNTR

The 48-base pair VNTR in exon 3 range from 2 to 11 repeats.

DRD4-7R, the 7-repeat (7R) variant of DRD4, has been linked to a susceptibility for developing ADHD in several meta-analyses and other psychological traits and disorders.^[13][14]

The frequency of the alleles varies greatly between populations, e.g., the 7-repeat version has high incidence in America and low in Asia.^[15] "Long" versions of polymorphisms are the alleles with 6 to 10 repeats. 7R appears to react less strongly to dopamine molecules.^[16]

The 48-base pair VNTR has been the subject of much speculation about its evolution and role in human behaviors cross-culturally. The 7R allele appears to have been selected for about 40,000 years ago.^[15] In 1999 Chen and colleagues^[17] observed that populations who migrated farther in the past 30,000 to 1,000 years ago had a higher frequency of 7R/long alleles. They also showed that nomadic populations had higher frequencies of 7R alleles than sedentary ones. More recently it was observed that the health status of nomadic Ariaal men was higher if they had 7R alleles. However, in recently sedentary (non-nomadic) Ariaal those with 7R alleles seemed to have slightly deteriorated health.^[18]

Novelty seeking

Despite early findings of an association between the DRD4 48bp VNTR and novelty seeking (a characteristic of exploratory and excitable people),^[19][20] a 2008 meta-analysis compared 36 published studies of novelty seeking and the polymorphism and found no effect. The meta-analysis of 11 studies did find that another polymorphism in the gene, the -521C/T, showed an association with novelty seeking.^[21] In any case, novelty-seeking behavior is probably mediated by several genes, and the variance attributable to DRD4 by itself is not particularly large.

Cognitive development

Several studies have suggested that parenting may affect the cognitive development of children with the 7-repeat allele of DRD4.^[22] Parenting that has maternal sensitivity, mindfulness, and autonomy–support at 15 months was found to alter children's executive functions at 18 to 20 months.^[22] Children with poorer quality parenting were more impulsive and sensation seeking than those with higher quality parenting.^[22] Higher quality parenting was associated with better effortful control in 4-year-olds.^[22]

Ligands

Chemical structures of representative D₄-preferring ligands.

Agonists

• WAY-100635: potent full agonist, with 5-HT_1A antagonistic component^[23]
• A-412,997: full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels^[24]
• ABT-724 - developed for treatment of erectile dysfunction^[25]
• ABT-670 - better oral bioavailability than ABT-724^[26]
• FAUC 316: partial agonist, > 8600-fold selective over other dopamine receptor subtypes^[27]
• FAUC 299: partial agonist^[27]
• (E)-1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes^[28]
• PIP3EA: partial agonist^[29]
• Flibanserin - partial agonist
• PD-168,077 - D₄ selective but also binds to α1A, α2C and 5HT_1A
• CP-226,269 - D₄ selective but also binds to D₂, D₃, α2A, α2C and 5HT_1A
• Ro10-5824 - partial agonist
• Roxindole (also D2 and D3 autoreceptor partial agonist, 5HT1A receptor agonist, serotonin reuptake inhibitor)
• Apomorphine also adenergic and 5ht agonist, most affinity for the D4 subtype

Antagonists

• A-381393: potent, subtype selective antagonist (>2700-fold)^[30]
• FAUC 213^[31]
• L-745,870^[32][33]
• L-750,667^[34]
• S 18126: also σ1 affin^[35]
• Fananserin - mixed 5-HT_2A / D₄ antagonist
• Clozapine, an atypical antipsychotic
• Buspirone, an anxiolytic

Inverse agonists

• FAUC F41: inverse agonist, subtype selectivity of more than 3 orders of magnitude over D₂ and D₃^[31][36]

See also

• dopamine hypothesis of psychosis

References

1. Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (Apr 1991). "Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine". Nature 350 (6319): 610–4. doi:10.1038/350610a0. PMID 1840645.
2. Ptácek R, Kuzelová H, Stefano GB (Sep 2011). "Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders". Medical Science Monitor 17 (9): RA215–RA220. doi:10.12659/MSM.881925. PMC 3560519. PMID 21873960.
3. Domschke K (Jul 2013). "Clinical and molecular genetics of psychotic depression". Schizophrenia Bulletin 39 (4): 766–75. doi:10.1093/schbul/sbt040. PMID 23512949.
4. McGeary J (Sep 2009). "The DRD4 exon 3 VNTR polymorphism and addiction-related phenotypes: a review". Pharmacology, Biochemistry, and Behavior 93 (3): 222–9. doi:10.1016/j.pbb.2009.03.010. PMID 19336242.
5. Cormier F, Muellner J, Corvol JC (Apr 2013). "Genetics of impulse control disorders in Parkinson's disease". Journal of Neural Transmission 120 (4): 665–71. doi:10.1007/s00702-012-0934-4. PMID 23232665.
6. Rask-Andersen M, Olszewski PK, Levine AS, Schiöth HB (Mar 2010). "Molecular mechanisms underlying anorexia nervosa: focus on human gene association studies and systems controlling food intake". Brain Research Reviews 62 (2): 147–64. doi:10.1016/j.brainresrev.2009.10.007. PMID 19931559.
7. Ptáček R, Kuželová H, Stefano GB, Raboch J, Kream RM (Apr 2013). "Targeted D4 dopamine receptors: implications for drug discovery and therapeutic development". Current Drug Targets 14 (4): 507–12. doi:10.2174/1389450111314040012. PMID 23469923.
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9. Catalano M, Nobile M, Novelli E, Nöthen MM, Smeraldi E (Oct 1993). "Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients". Biological Psychiatry 34 (7): 459–64. doi:10.1016/0006-3223(93)90236-7. PMID 8268330.
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11. Gene Overview of All Published Schizophrenia-Association Studies for DRD4 - SzGene database at Schizophrenia Research Forum.
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14. Faraone SV, Doyle AE, Mick E, Biederman J (Jul 2001). "Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder". The American Journal of Psychiatry 158 (7): 1052–7. doi:10.1176/appi.ajp.158.7.1052. PMID 11431226.
15. Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL, Ryder OA, Spence MA, Swanson JM, Moyzis RK (May 2004). "The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus". American Journal of Human Genetics 74 (5): 931–44. doi:10.1086/420854. PMC 1181986. PMID 15077199.
16. Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH (Sep 1995). "Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants". Journal of Neurochemistry 65 (3): 1157–1165. doi:10.1046/j.1471-4159.1995.65031157.x. PMID 7643093.
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18. Eisenberg DT, Campbell B, Gray PB, Sorenson MD (2008). "Dopamine receptor genetic polymorphisms and body composition in undernourished pastoralists: an exploration of nutrition indices among nomadic and recently settled Ariaal men of northern Kenya". BMC Evolutionary Biology 8: 173. doi:10.1186/1471-2148-8-173. PMC 2440754. PMID 18544160.
19. Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennett ER, Nemanov L, Katz M, Belmaker RH (Jan 1996). "Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking". Nature Genetics 12 (1): 78–80. doi:10.1038/ng0196-78. PMID 8528256.
20. Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH (Jan 1996). "Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking". Nature Genetics 12 (1): 81–4. doi:10.1038/ng0196-81. PMID 8528258.
21. Munafò MR, Yalcin B, Willis-Owen SA, Flint J (Jan 2008). "Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data". Biological Psychiatry 63 (2): 197–206. doi:10.1016/j.biopsych.2007.04.006. PMID 17574217.
22. Posner MI, Rothbart MK, Sheese BE, Voelker P (May 2012). "Control networks and neuromodulators of early development". Developmental Psychology 48 (3): 827–35. doi:10.1037/a0025530. PMID 21942663.
23. Chemel BR, Roth BL, Armbruster B, Watts VJ, Nichols DE (Oct 2006). "WAY-100635 is a potent dopamine D4 receptor agonist". Psychopharmacology 188 (2): 244–51. doi:10.1007/s00213-006-0490-4. PMID 16915381.
24. Moreland RB, Patel M, Hsieh GC, Wetter JM, Marsh K, Brioni JD (Sep 2005). "A-412997 is a selective dopamine D4 receptor agonist in rats". Pharmacology, Biochemistry, and Behavior 82 (1): 140–7. doi:10.1016/j.pbb.2005.08.001. PMID 16153699.
25. Cowart M, Latshaw SP, Bhatia P, Daanen JF, Rohde J, Nelson SL, Patel M, Kolasa T, Nakane M, Uchic ME, Miller LN, Terranova MA, Chang R, Donnelly-Roberts DL, Namovic MT, Hollingsworth PR, Martino BR, Lynch JJ, Sullivan JP, Hsieh GC, Moreland RB, Brioni JD, Stewart AO (Jul 2004). "Discovery of 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a dopaminergic agent with a novel mode of action for the potential treatment of erectile dysfunction". Journal of Medicinal Chemistry 47 (15): 3853–64. doi:10.1021/jm030505a. PMID 15239663.
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External links

• "Dopamine Receptors: D₄". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• Current Research on the DRD₄ Gene
• Receptors, Dopamine D4 at the US National Library of Medicine Medical Subject Headings (MeSH)
• Marisa Wilson. "Are you a thrill seeker??". Davidson College. Retrieved 2008-04-05.
• "The D4DR Gene". D4DR Club. Retrieved 2008-04-05.

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