Dopamine receptor D4

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Dopamine receptor D4
Identifiers
Symbols DRD4 ; D4DR
External IDs OMIM126452 MGI94926 HomoloGene20215 IUPHAR: 217 ChEMBL: 219 GeneCards: DRD4 Gene
RNA expression pattern
PBB GE DRD4 208215 x at tn.png
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 [1] [2]

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[edit]

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 I.[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 [edit]

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[edit]

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[edit]

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[edit]

Chemical structures of representative D4-preferring ligands.

Agonists[edit]

Antagonists[edit]

Inverse agonists[edit]

See also[edit]

References[edit]

  1. ^ Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB et al. (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). PMID 21873960. 
  3. ^ Domschke K (Jul 2013). "Clinical and molecular genetics of psychotic depression". Schizophrenia Bulletin 39 (4). 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). 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). 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). 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). PMID 23469923. 
  8. ^ Neve KA, Seamans JK, Trantham-Davidson H (Aug 2004). "Dopamine receptor signaling". Journal of Receptor and Signal Transduction Research 24 (3): 165–205. doi:10.1081/RRS-200029981. PMID 15521361. 
  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. 
  10. ^ Thapar A, Langley K, Owen MJ, O'Donovan MC (Dec 2007). "Advances in genetic findings on attention deficit hyperactivity disorder". Psychological Medicine 37 (12): 1681–92. doi:10.1017/S0033291707000773. PMID 17506925. 
  11. ^ Gene Overview of All Published Schizophrenia-Association Studies for DRD4 - SzGene database at Schizophrenia Research Forum.
  12. ^ 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. 
  13. ^ Wu J, Xiao H, Sun H, Zou L, Zhu LQ (Jun 2012). "Role of dopamine receptors in ADHD: a systematic meta-analysis". Molecular Neurobiology 45 (3): 605–20. doi:10.1007/s12035-012-8278-5. PMID 22610946. 
  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. ^ a b Wang E, Ding YC, Flodman P, Kidd JR, Kidd KK, Grady DL et al. (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. 
  17. ^ Chen CS, Burton M, Greenberger E, Dmitrieva J (September 1999). "Population migration and the variation of dopamine D4 receptor (DRD4) allele frequencies around the globe". Evolution and Human Behavior 20 (5): 309–324. doi:10.1016/S1090-5138(99)00015-X. 
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External links[edit]

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