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20-September-2008 09:55:50 - receptor D4 The correct title of this article is Dopamine receptor D4. It appears incorrectly here because of technical restrictions. Dopamine receptor D4 Identifiers Symbols DRD4; D4DR External IDs OMIM: 126452 MGI: 94926 HomoloGene: 20215 Gene ontology Molecular function: rhodopsin-like receptor activity receptor activity dopamine receptor activity Cellular component: plasma membrane integral to plasma membrane membrane integral to membrane Biological process: signal transduction G-protein coupled receptor protein signaling pathway dopamine receptor signaling pathway synaptic transmission 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 1 Polymorphism 2 Novelty seeking 3 Ligands 3.1 Agonists 3.2 Antagonists 3.3 Inverse agonists 4 See also 5 References 6 External links 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.12 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 ADHD3 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 Novelty seeking In two studies published in Nature Genetics56, 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. Ligands Chemical structures of a D4-prefering ligands. Chemical structures of a D4-prefering ligands. Agonists WAY-100635: potent full agonist, with 5-HT1A antagonistic component7 A-412,997: full agonist, 100-fold selective over a panel of seventy different receptors and ion channels8 FAUC 316: partial agonist, 8600-fold selective over other dopamine receptor subtypes9 FAUC 299: partial agonist9 E-1-aryl-3-4-pyridinepiperazin-1-ylpropanone oximes10 ABT-670: orally bioavailable11 PIP3EA: partial agonist12 ABT-724 - partial agonist13 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 Antagonists A-381393: potent, subtype selective antagonist 2700-fold14 FAUC 21315 L-745,8701617 L-750,66718 S 18126: also σ1 affin19 Fananserin - mixed 5-HT2A / D4 antagonist Inverse agonists FAUC F41: inverse agonist, subtype selectivity of more than 3 orders of magnitude over D2 and D31520 See also dopamine dopamine hypothesis of psychosis References ^ 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. ^ Entrez Gene: DRD4 dopamine receptor D4. ^ Faraone SV, Doyle AE, Mick E, Biederman J 2001. Meta-analysis of the association between the 7-repeat allele of the dopamine D4 receptor gene and attention deficit hyperactivity disorder. Am J Psychiatry 158 7: 1052-7. doi:10.1176/appi.ajp.158.7.1052. PMID 11431226. ^ 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 inactive 2008-06-23. PMID 7643093. ^ 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. ^ 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. ^ 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. ^ 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. ^ 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. ^ Kolasa T, Matulenko MA, Hakeem AA, et al August 2006. 1-aryl-3-4-pyridine-2-ylpiperazin-1-ylpropan-1-one oximes as potent dopamine D4 receptor agonists for the treatment of erectile dysfunction. J. Med. Chem. 49 17: 5093-109. doi:10.1021/jm060279f. PMID 16913699. ^ Patel MV, Kolasa T, Mortell K, et al December 2006. Discovery of 3-methyl-N-1-oxy-3',4',5',6'-tetrahydro-2'H-2,4'-bipyridine-1'-ylmethylbenzamide ABT-670, an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction. J. Med. Chem. 49 25: 7450-65. doi:10.1021/jm060662k. PMID 17149874. ^ Enguehard-Gueiffier C, Hübner H, El Hakmaoui A, et al June 2006. 2-4-phenylpiperazin-1-ylmethylimidazodiazines as selective D4-ligands. Induction of penile erection by 2-4-2-methoxyphenylpiperazin-1-ylmethylimidazo1,2-apyridine PIP3EA, a potent and selective D4 partial agonist. J. Med. Chem. 49 13: 3938-47. doi:10.1021/jm060166w. PMID 16789750. ^ Cowart M, Latshaw SP, Bhatia P, et al July 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. J. Med. Chem. 47 15: 3853-64. doi:10.1021/jm030505a. PMID 15239663. ^ Nakane M, Cowart MD, Hsieh GC, et al July 2005. 2-4-3,4-Dimethylphenylpiperazin-1-ylmethyl-1H benzoimidazole A-381393, a selective dopamine D4 receptor antagonist. Neuropharmacology 49 1: 112-21. doi:10.1016/j.neuropharm.2005.02.004. PMID 15992586. ^ a b Prante O, Tietze R, Hocke C, Löber S, Hübner H, Kuwert T, Gmeiner P 2008. Synthesis, Radiofluorination, and In Vitro Evaluation of Pyrazolo1,5-apyridine-Based Dopamine D4 Receptor Ligands: Discovery of an Inverse Agonist Radioligand for PET. J. Med. Chem. 51: 1800. doi:10.1021/jm701375u. PMID 18307287. ^ Kulagowski JJ, Broughton HB, Curtis NR, et al May 1996. 3-4-4-Chlorophenylpiperazin-1-yl-methyl-1H-pyrrolo-2,3-b-pyridine: an antagonist with high affinity and selectivity for the human dopamine D4 receptor. J. Med. Chem. 39 10: 1941-2. doi:10.1021/jm9600712. PMID 8642550. ^ Patel S, Freedman S, Chapman KL, et al November 1997. Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor. J. Pharmacol. Exp. Ther. 283 2: 636-47. PMID 9353380. ^ Patel S, Patel S, Marwood R, et al December 1996. Identification and pharmacological characterization of 125IL-750,667, a novel radioligand for the dopamine D4 receptor. Mol. Pharmacol. 50 6: 1658-64. PMID 8967990. ^ Millan MJ, Newman-Tancredi A, Brocco M, et al October 1998. S 18126 2-4-2,3-dihydrobenzo1,4dioxin-6-ylpiperazin-1-yl methylindan-2-yl, a potent, selective and competitive antagonist at dopamine D4 receptors: an in vitro and in vivo comparison with L 745,870 3-4-4-chlorophenylpiperazin-1-ylmethyl-1H-pyrrolo2, 3bpyridine and raclopride. J. Pharmacol. Exp. Ther. 287 1: 167-86. PMID 9765336. ^ Lanig H, Utz W, Gmeiner P 2001. Comparative molecular field analysis of dopamine D4 receptor antagonists including 3-4-4-chlorophenylpiperazin-1-ylmethylpyrazolo1,5-apyridine FAUC 113, 3-4-4-chlorophenylpiperazin-1-ylmethyl-1H-pyrrolo-2,3-bpyridine L-745,870, and clozapine. J. Med. Chem. 44 8: 1151-7. doi:10.1021/jm001055e. PMID 11312915. External links MeSH Receptors,+Dopamine+D4 MR Wilson. Are you a thrill seeker??. Davidson College. Retrieved on 2008-04-05. The D4DR Gene. D4DR Club. Retrieved on 2008-04-05. This transmembrane receptor-related article is a stub. This article incorporates text from the United States National Library of Medicine, which is in the public domain. v d e Transmembrane receptor: G protein-coupled receptors Class A: Rhodopsin like Adrenergic α1 A, B, D, α2 A, B, C, β1, β2, β3 Eicosanoid CysLT 1, 2, LTB4 1, 2, FPRL1, OXE, Prostaglandin DP, EP 1, 2, 3, 4, PGF, Prostacyclin, Thromboxane Neuropeptide B/W 1, 2, FF 1, 2, S, Y 1, 2, 4, 5 Orphan GPR 1, 3, 4, 6, 12, 15, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 31, 32, 33, 34, 35, 37, 39, 42, 44, 45, 50, 52, 55, 61, 62, 63, 65, 68, 75, 77, 78, 79, 82, 83, 84, 85, 87, 88, 92, 101, 103, 119, 120, 132, 135, 139, 141, 142, 146, 148, 149, 150, 151, 152, 153, 160, 161, 162, 171, 172, 173, 174, 176, 177, 182 Purinergics Adenosine A1, A2a, A2b, A3, P2Y, 1, 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14 Serotonin all but 5-HT3 5-HT1 A, B, D, E, F, 5-HT2 A, B, C, 5-HT 4, 5A, 6, 7 Other Acetylcholine M1, M2, M3, M4, M5 - Adrenomedullin - Anaphylatoxin C3a, C5a - Angiotensin 1, 2 - Apelin - Bile acid - Bombesin BRS3, GRPR, NMBR - Bradykinin B1, B2 - Cannabinoid CB1, CB2 - Chemokine - Cholecystokinin A, B - Dopamine D1, D2, D3, D4, D5 - EBI2 - Endothelin A, B - Estrogen - Formyl peptide 1, L1, L2 - Free fatty acid 1, 2, 3, 4 - FSH - Galanin 1, 2, 3 - Gonadotropin-releasing hormone 1, 2 - Ghrelin - Histamine H1, H2, H3, H4 - Kisspeptin - Luteinizing hormone/choriogonadotropin - Lysophospholipid 1, 2, 3, 4, 5, 6, 7, 8 - MAS 1, 1L, D, E, F, G, X1, X2, X3, X4 - Melanocortin 1, 2, 3, 4, 5 - MCHR 1, 2 - Melatonin 1A, 1B- Motilin - neuromedin B, U 1, 2 - Neurotensin 1, 2 - Opioid Delta, Kappa, Mu, Nociceptin, but not Sigma - Olfactory - Opsin 3, 4, 5, 1LW, 1MW, 1SW, RGR, RRH - Orexin 1, 2 - Oxytocin - Oxoglutarate - PAF - Prokineticin 1, 2 - Prolactin-releasing peptide - Protease-activated 1, 2, 3, 4 - Relaxin 1, 2, 3, 4 - Somatostatin 1, 2, 3, 4, 5 - SREB - Succinate - TAAR 1, 2, 3, 5, 6, 8, 9 - Tachykinin 1, 2, 3 - Thyrotropin - Thyrotropin-releasing hormone - Urotensin-II - Vasopressin 1A, 1B, 2 Class B: Secretin like Brain-specific angiogenesis inhibitor 1, 2, 3 - Cadherin 1, 2, 3 - Calcitonin - CD97 - Corticotropin-releasing hormone 1, 2 - EMR 1, 2, 3 - Glucagon GR, GIPR, GLP1R, GLP2R - Growth hormone releasing hormone - PACAPR1- GPR 56, 64, 97, 98, 110, 111, 112, 113, 114, 115, 116, 123, 124, 125, 126, 128, 133, 143, 144, 157 - Latrophilin 1, 2, 3, ELTD1 - Parathyroid hormone 1, 2 - Secretin - Vasoactive intestinal peptide 1, 2 Class C: Metabotropic glutamate / pheromone Calcium-sensing receptor - GABA B 1, 2 - Glutamate receptor Metabotropic glutamate 1, 2, 3, 4, 5, 6, 7, 8 - GPRC6A - GPR 156, 158, 179 - RAIG 1, 2, 3, 4 - Taste receptors TAS1R 1, 2, 3 TAS2R 1, 3, 4, 5, 8, 9, 10, 12, 13, 14, 16, 38, 39, 40, 41, 43, 44, 45, 46, 47, 48, 49, 50 Frizzled / Smoothened Frizzled 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 - Smoothened Retrieved from http://en..org/wiki/Dopamine_receptor_D4 Categories: Genes on chromosome 11 | Human proteins | Transmembrane receptor stubs | G protein coupled receptorsHidden categories: Pages with DOIs broken since 2008 | Protein pages needing a picture Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page This page was last modified on 8 August 2008, at 14:50
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