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Dopamine receptor D4

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Template:PBB 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 including schizophrenia, Parkinsons disease, bipolar disorder, addictive behaviors, and eating disorders such as anorexia nervosa, bulimia nervosa and binge eating.

It is also a target for drugs which treat schizophrenia and Parkinson disease. 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.[2]

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 I.[3]
  • 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,[4] schizophrenia,[5] and the personality trait of novelty seeking.[6]

48-base pair VNTR

The 48-base pair VNTR in exon 3 range from 2 to 11 repeats. The frequency of the alleles varies greatly between populations, e.g., the 7-repeat version has high incidence in America and low in Asia.[7] "Long" versions of polymorphisms are the alleles with 6 to 10 repeats. 7R appears to react less strongly to dopamine molecules.[8]

The 'DRD4 long' variant, or more specifically the 7 repeat (7R), has been linked to a susceptibility for developing ADHD in several meta-analyses [9] [10] and other psychological traits and disorders.

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.[7] In 1999 Chen and colleagues[11] 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.[12]

Novelty seeking

Despite early findings of an association between the DRD4 48bp VNTR and novelty seeking (a characteristic of exploratory and excitable people),[13][14] 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.[15] 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.[16] 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.[16] Children with poorer quality parenting were more impulsive and sensation seeking than those with higher quality parenting.[16] Higher quality parenting was associated with better effortful control in 4-year-olds.[16]

Ligands

Chemical structures of representative D4-preferring ligands.

Agonists

Antagonists

Inverse agonists

See also

References

  1. ^ Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (April 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Neve KA, Seamans JK, Trantham-Davidson H (August 2004). "Dopamine receptor signaling". J. Recept. Signal Transduct. Res. 24 (3): 165–205. doi:10.1081/RRS-200029981. PMID 15521361.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Catalano M, Nobile M, Novelli E, Nöthen MM, Smeraldi E (October 1993). "Distribution of a novel mutation in the first exon of the human dopamine D4 receptor gene in psychotic patients". Biol. Psychiatry. 34 (7): 459–64. doi:10.1016/0006-3223(93)90236-7. PMID 8268330.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Thapar A, Langley K, Owen MJ, O'Donovan MC (December 2007). "Advances in genetic findings on attention deficit hyperactivity disorder". Psychol Med. 37 (12): 1681–92. doi:10.1017/S0033291707000773. PMID 17506925.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Gene Overview of All Published Schizophrenia-Association Studies for DRD4 - SzGene database at Schizophrenia Research Forum.
  6. ^ Munafò MR, Yalcin B, Willis-Owen SA, Flint J (January 2008). "Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data". Biol. Psychiatry. 63 (2): 197–206. doi:10.1016/j.biopsych.2007.04.006. PMID 17574217.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ a b 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". Am. J. Hum. Genet. 74 (5): 931–44. doi:10.1086/420854. PMC 1181986. PMID 15077199.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, Van Tol HH (September 1995). "Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants". J Neurochem. 65 (3): 1157–1165. doi:10.1046/j.1471-4159.1995.65031157.x. PMID 7643093.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  12. ^ 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 Evol. Biol. 8: 173. doi:10.1186/1471-2148-8-173. PMC 2440754. PMID 18544160.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  13. ^ Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennett ER, Nemanov L, Katz M, Belmaker RH (January 1996). "Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking". Nat. Genet. 12 (1): 78–80. doi:10.1038/ng0196-78. PMID 8528256.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH (January 1996). "Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking". Nat. Genet. 12 (1): 81–4. doi:10.1038/ng0196-81. PMID 8528258.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Munafo MR, Yalcin B, Willis-Owen SA, Flint J. (2008). "Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data". Biol Psychiatry. 63 (2): 197–206. doi:10.1016/j.biopsych.2007.04.006. PMID 17574217.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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External links

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

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