Dopamine receptor D4

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The correct title of this article is Dopamine receptor D4. It appears incorrectly here because of technical restrictions.
Dopamine receptor D4
Identifiers
Symbol(s) DRD4; D4DR
External IDs OMIM: 126452 MGI: 94926 HomoloGene: 20215
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 1815 13491
Ensembl ENSG00000069696 ENSMUSG00000025496
Uniprot n/a Q7TT80
Refseq NM_000797 (mRNA)
NP_000788 (protein)		 NM_007878 (mRNA)
NP_031904 (protein)
Location Chr 11: 0.63 - 0.63 Mb Chr 7: 141.14 - 141.15 Mb
Pubmed search [1] [2]

The dopamine receptor D4 is a G protein-coupled receptor encoded by the DRD4 gene. As with other dopamine receptor subtypes, the D4 receptor is activated by the neurotransmitter dopamine. 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 adenylyl cyclase, thereby reducing the intracellular concentration of the second messenger cyclic AMP.

Contents

[edit] Polymorphism

This gene contains a polymorphic number (2-10 copies) of tandem 48 nt repeats where the 4 repeat (4R) is the most commonly expressed while 2R and 7R are less common.[1][2] Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder, and the personality trait of novelty seeking. Particularly, a specific allele (known as the 'DRD4 long' variant, or more specifically the 7 repeat (7R) has been loosely linked to a susceptibility for developing ADHD[3] and other psychological traits and disorders, like autism.

The receptor expressed by the D4DR gene is responsible in part for detecting the neurotransmitter dopamine which mediates (among other things) pleasure and emotion. The 7 repeat (7R) elongated copy of this gene appears to react less strongly to dopamine molecules.[4]

[edit] Novelty seeking

In two studies published in Nature Genetics[5][6], subjects filled out personality questionnaires and had blood taken for genetic analysis. The scientists found that those whose answers showed them to be exploratory and excitable — two hallmarks of novelty-seeking — also possessed a longer 7 repeat (7R) version of D4DR, compared with those who are more reserved and reflective. A few other studies have replicated these results (including two done in Japan) but at least one has found no such correlation. In any case, thrill-seeking behavior is probably mediated by several genes, and the variance attributable to D4DR by itself is not particularly large.


[edit] Ligands

Chemical structures of a D4-prefering ligands.
Chemical structures of a D4-prefering ligands.
  • WAY-100635, potent full agonist, with 5-HT1A antagonistic component[7]
  • A-412,997, full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels[8]
  • FAUC 316, partial agonist, > 8600-fold selective over other dopamine receptor subtypes[9]
  • FAUC 299, partial agonist[9]
  • FAUC 213, antagonist[10]
  • FAUC F41, inverse agonist, subtype selectivity of more than 3 orders of magnitude over D2 and D3[10][11]
  • ABT-724 - partial agonist
  • PD-168,077 - D4 selective but also binds to α1A, α2C and 5HT1A
  • CP-226,269 - D4 selective but also binds to D2, D3, α2A, α2C and 5HT1A
  • Ro10-5824 - partial agonist

[edit] See also

[edit] References

  1. ^ 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. PMID 15077199. 
  2. ^ Entrez Gene: DRD4 dopamine receptor D4.
  3. ^ Faraone SV, Doyle AE, Mick E, Biederman J (2001). "Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder". Am J Psychiatry 158 (7): 1052–7. doi:10.1176/appi.ajp.158.7.1052. PMID 11431226. 
  4. ^ 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): 1157–65. doi:10.1046/j.1471-4159.1995.65031157.x. PMID 7643093. 
  5. ^ Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennett ER, Nemanov L, Katz M, Belmaker RH (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. 
  6. ^ Benjamin J, Li L, Patterson C, Greenberg BD, Murphy DL, Hamer DH (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. 
  7. ^ Chemel BR, Roth BL, Armbruster B, Watts VJ, Nichols DE (2006). "WAY-100635 is a potent dopamine D4 receptor agonist". Psychopharmacology (Berl.) 188 (2): 244–51. doi:10.1007/s00213-006-0490-4. PMID 16915381. 
  8. ^ Moreland RB, Patel M, Hsieh GC, Wetter JM, Marsh K, Brioni JD (2005). "A-412997 is a selective dopamine D4 receptor agonist in rats". Pharmacol. Biochem. Behav. 82 (1): 140–7. doi:10.1016/j.pbb.2005.08.001. PMID 16153699. 
  9. ^ a b Hübner H, Kraxner J, Gmeiner P (2000). "Cyanoindole derivatives as highly selective dopamine D4 receptor partial agonists: solid-phase synthesis, binding assays, and functional experiments". J. Med. Chem. 43 (23): 4563–9. doi:10.1021/jm0009989. PMID 11087581. 
  10. ^ a b Prante O, Tietze R, Hocke C, Löber S, Hübner H, Kuwert T, Gmeiner P (2008). "Synthesis, Radiofluorination, and In Vitro Evaluation of Pyrazolo[1,5-a]pyridine-Based Dopamine D4 Receptor Ligands: Discovery of an Inverse Agonist Radioligand for PET". J. Med. Chem. 51: 1800. doi:10.1021/jm701375u. PMID 18307287. 
  11. ^ Lanig H, Utz W, Gmeiner P (2001). "Comparative molecular field analysis of dopamine D4 receptor antagonists including 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113), 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-1H-pyrrolo-[2,3-b]pyridine (L-745,870), and clozapine". J. Med. Chem. 44 (8): 1151–7. doi:10.1021/jm001055e. PMID 11312915. 

[edit] External links

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v • d • e
Transmembrane receptor: G protein-coupled receptors
Class A: Rhodopsin like
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Class B: Secretin like
Class C: Metabotropic
glutamate / pheromone
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Frizzled (1, 2, 3, 4, 5, 6, 7, 8, 9, 10) - Smoothened