In humans, D5 receptor is encoded on the chromosome 4p15.1–p15.3. The gene lacks introns and encodes a product of 477 amino acids. Two pseudogenes for D5 receptor exist that share 98% sequence with each other and 95% sequence with the functional DRD5 gene. These genes contain several in-framestop codons that prevent these genes from transcribing a functional protein.
Polymorphisms in the DRD5 gene, which encodes dopamine receptor D5, have been suggested to play a role in the initiation of smoking. In a study on the association of four polymorphisms of this gene with smoking, a statistical analysis suggested that there may exist a haplotype of DRD5 that is protective against initiation of smoking.
Dinucleotide repeats of DRD5 gene are associated with ADHD in humans. 136-bp allele of the gene was shown to be a protective factor against developing this disorder, and 146-bp allele of DRD5 was shown to be a risk factor for it. There exist two types of the 146-bp allele of DRD5, a long and a short one. The short dinucleotide repeat allele is associated with ADHD, but not the long one. Another allele of DRD5 that is moderately associated with ADHD susceptibility is 150 bp.
In a rat model of ADHD, low density of D5 was found in the hippocampalpyramidal cellsomas. Deficiency in D5 receptors may contribute to learning problems that may be associated with ADHD.
D5 receptors may be involved in burst firing of subthalamic nucleus neurons in 6-OHDA rat model of Parkinson's disease. In this animal model, blockage of D5 receptors with flupentixol reduces burst firing and improves motor deficits. Studies show that DRD5 T978C polymorphism is not associated with the susceptibility to PD, nor with the risk of developing motor fluctuations or hallucinations in PD.
Several polymorphisms in DRD5 genes have been associated with susceptibility to schizophrenia. The 148 bp allele of DRD5 was linked to increased risk of schizophrenia. Some single-nucleotide polymorphisms in this gene, including changes in rs77434921, rs1800762, rs77434921, and rs1800762, in northern Han Chinese population.
D5 receptor is believed to participate in modulation of psychostimulant-induced locomotion. Mice lacking D5 receptors show increased motor response to administration of methamphetamine than wild type mice, which suggests that these receptors have a role in controlling motor activity.
Regulation of blood pressure
D5 receptor may be involved in modulation of the neuronal pathways that regulate blood pressure. Mice lacking this receptor in their brains showed hypertension and elevated blood pressure, which may have been caused by increased sympathetic tone. D5 receptors that are expressed in kidneys are also involved in the regulation of blood pressure via modulating expression of renalase and excretion of sodium, and disturbance of these processes can contribute to hypertension as well.
The D1 and D5 receptors have a high degree of structural homology and few ligands are available that can distinguish between them as yet. However, there is a number of ligands that are selective for D1/5 over the other dopamine receptors. The recent development of a selective D5 antagonist has allowed the action of D1-mediated responses to be studied in the absence of a D5 component, but no selective D5 agonists are yet available.
D5 receptors show higher affinity for agonists and lower affinity for antagonists than D1 receptors.
The high degree of homology between D5 and D1 receptors and their affinity for drugs with similar pharmacological profile complicate distinguishing between them in research. Antibody staining these two receptors separately is suggested to be inefficient. However, expression of D5 receptors has been assessed using immunohistochemistry. In this technique, two peptides were obtained from third exracellular loop and third intracellular loop of the receptor, and antisera were developed for staining the receptor in frozen mouse brain tissue. A method involving mRNA probes for in situ hybridization has been developed, which allowed to separately examine the expression of D1 and D5 receptors in the mouse brain.
^ abcSunahara RK, Guan HC, O'Dowd BF, Seeman P, Laurier LG, Ng G, George SR, Torchia J, Van Tol HH, Niznik HB (1991). "Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1". Nature. 350 (6319): 614–9. doi:10.1038/350614a0. PMID1826762.
^Eubanks JH, Altherr M, Wagner-McPherson C, McPherson JD, Wasmuth JJ, Evans GA (1992). "Localization of the D5 dopamine receptor gene to human chromosome 4p15.1-p15.3, centromeric to the Huntington's disease locus". Genomics. 12 (3): 510–6. doi:10.1016/0888-7543(92)90442-u. PMID1532789.
^Miyazaki I, Asanuma M, Diaz-Corrales FJ, Miyoshi K, Ogawa N (2004). "Direct evidence for expression of dopamine receptors in astrocytes from basal ganglia". Brain Research. 1029 (1): 120–3. doi:10.1016/j.brainres.2004.09.014. PMID15533323.
^Prado C, Bernales S, Pacheco R (2013). "Modulation of T-cell mediated immunity by dopamine receptor d5". Endocrine, Metabolic & Immune Disorders Drug Targets. 13 (2): 184–94. doi:10.2174/1871530311313020007. PMID23701196.
^Sullivan PF, Neale MC, Silverman MA, Harris-Kerr C, Myakishev MV, Wormley B, Webb BT, Ma Y, Kendler KS, Straub RE (April 2001). "An association study of DRD5 with smoking initiation and progression to nicotine dependence". Am. J. Med. Genet. 105 (3): 259–65. doi:10.1002/ajmg.1301. PMID11353446.
^Kim BN, Kang D, Cho SC, Park TW, Lim MH, Chung YC, Kim JW, Hwang JW, Yoo HJ, Chung US, Son JW, Yang JC, Chung SK, Lee JY, Jung YW (2009). "Shorter dinucleotide repeat length in the DRD5 gene is associated with attention deficit hyperactivity disorder". Psychiatric Genetics. 19 (1): 57. doi:10.1097/YPG.0b013e328320803c. PMID19125111.
^Squassina A, Lanktree M, De Luca V, Jain U, Krinsky M, Kennedy JL, Muglia P (2008). "Investigation of the dopamine D5 receptor gene (DRD5) in adult attention deficit hyperactivity disorder". Neuroscience Letters. 432 (1): 50–3. doi:10.1016/j.neulet.2007.12.003. PMID18164132.
^Medin T, Rinholm JE, Owe SG, Sagvolden T, Gjedde A, Storm-Mathisen J, Bergersen LH (2013). "Low dopamine D5 receptor density in hippocampus in an animal model of attention-deficit/hyperactivity disorder (ADHD)". Neuroscience. 242: 11–20. doi:10.1016/j.neuroscience.2013.03.036. PMID23541742.
^Wang J, Liu ZL, Chen B (July 2001). "Dopamine D5 receptor gene polymorphism and the risk of levodopa-induced motor fluctuations in patients with Parkinson's disease". Neuroscience Letters. 308 (1): 21–4. doi:10.1016/S0304-3940(01)01971-1. PMID11445276.
^Wang J, Zhao C, Chen B, Liu Z (January 2004). "Polymorphisms of dopamine receptor and transporter genes and hallucinations in Parkinson's disease". Neuroscience Letters. 355 (3): 193–6. doi:10.1016/j.neulet.2003.11.006. PMID14732464.
^ abMohr P, Decker M, Enzensperger C, Lehmann J (2006). "Dopamine/serotonin receptor ligands. 12(1): SAR studies on hexahydro-dibenz[d,g]azecines lead to 4-chloro-7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecin-3-ol, the first picomolar D5-selective dopamine-receptor antagonist". J. Med. Chem. 49 (6): 2110–2116. doi:10.1021/jm051237e. PMID16539400.
^Ulfers AL, McMurry JL, Kendall DA, Mierke DF (2002). "Structure of the third intracellular loop of the human cannabinoid 1 receptor". Biochemistry. 41 (38): 11344–50. doi:10.1021/bi0259610. PMID12234176.
^Liu F, Wan Q, Pristupa ZB, Yu XM, Wang YT, Niznik HB (2000). "Direct protein–protein coupling enables cross-talk between dopamine D5 and gamma-aminobutyric acid A receptors". Nature. 403 (6767): 274–80. doi:10.1038/35002014. PMID10659839.
^Missale C, Fiorentini C, Collo G, Spano P (2010). "The neurobiology of dopamine receptors: Evolution from the dual concept to heterodimer complexes". Journal of Receptors and Signal Transduction. 30 (5): 347–54. doi:10.3109/10799893.2010.506192. PMID20684667.
^Heyer J, Xiao Q, Bugaj-Gaweda B, Ramboz S, Unterbeck A (2002). "Conditional inactivation of the dopamine receptor 5 gene: Flanking the Drd5 gene with loxP sites". Genesis. 32 (2): 102–4. doi:10.1002/gene.10069. PMID11857790.
Eubanks JH, Altherr M, Wagner-McPherson C, McPherson JD, Wasmuth JJ, Evans GA (1992). "Localization of the D5 dopamine receptor gene to human chromosome 4p15.1-p15.3, centromeric to the Huntington's disease locus". Genomics. 12 (3): 510–516. doi:10.1016/0888-7543(92)90442-U. PMID1532789.
Sunahara RK, Guan HC, O'Dowd BF, Seeman P, Laurier LG, Ng G, George SR, Torchia J, Van Tol HH, Niznik HB (1991). "Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1". Nature. 350 (6319): 614–619. doi:10.1038/350614a0. PMID1826762.
Weinshank RL, Adham N, Macchi M, Olsen MA, Branchek TA, Hartig PR (1991). "Molecular cloning and characterization of a high affinity dopamine receptor (D1 beta) and its pseudogene". J. Biol. Chem. 266 (33): 22427–35. PMID1834671.
Sobell JL, Lind TJ, Sigurdson DC, Zald DH, Snitz BE, Grove WM, Heston LL, Sommer SS (1995). "The D5 dopamine receptor gene in schizophrenia: identification of a nonsense change and multiple missense changes but lack of association with disease". Hum. Mol. Genet. 4 (4): 507–514. doi:10.1093/hmg/4.4.507. PMID7633397.
Beischlag TV, Marchese A, Meador-Woodruff JH, Damask SP, O'Dowd BF, Tyndale RF, van Tol HH, Seeman P, Niznik HB (1995). "The human dopamine D5 receptor gene: cloning and characterization of the 5'-flanking and promoter region". Biochemistry. 34 (17): 5960–5970. doi:10.1021/bi00017a025. PMID7727453.
Sherrington R, Mankoo B, Attwood J, Kalsi G, Curtis D, Buetow K, Povey S, Gurling H (1994). "Cloning of the human dopamine D5 receptor gene and identification of a highly polymorphic microsatellite for the DRD5 locus that shows tight linkage to the chromosome 4p reference marker RAF1P1". Genomics. 18 (2): 423–425. doi:10.1006/geno.1993.1489. PMID8288248.
Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES (1999). "Characterization of single-nucleotide polymorphisms in coding regions of human genes". Nat. Genet. 22 (3): 231–238. doi:10.1038/10290. PMID10391209.
Liu F, Wan Q, Pristupa ZB, Yu XM, Wang YT, Niznik HB (2000). "Direct protein–protein coupling enables cross-talk between dopamine D5 and gamma-aminobutyric acid A receptors". Nature. 403 (6767): 274–280. doi:10.1038/35002014. PMID10659839.
Misbahuddin A, Placzek MR, Chaudhuri KR, Wood NW, Bhatia KP, Warner TT (2004). "A polymorphism in the dopamine receptor DRD5 is associated with blepharospasm". Neurology. 58 (1): 124–6. doi:10.1212/wnl.58.1.124. PMID11781417.