D5 receptor is a subtype of the dopamine receptor that has a 10-fold higher affinity for dopamine than theD1 subtype.[6] The D5 subtype is aG-protein coupled receptor, which promotes synthesis ofcAMP byadenylyl cyclase via activation ofGαs/olf family of G proteins.[7][8] Both D5 and D1 subtypes activateadenylyl cyclase. D1 receptors were shown to stimulate monophasicdose-dependent accumulation of cAMP in response todopamine, and the D5 receptors were able to stimulate biphasic accumulation of cAMP under the same conditions, suggesting that D5 receptors may use a different system of secondary messengers than D1 receptors.[9]
D5 receptor is highlyhomologous to theD1 receptor. Theiramino acid sequences are 49%[6] to 80%[12] identical. D5 receptor has a longC-terminus of 93amino acids, accounting for 26% of the entire protein. In spite of the high degree of homology between D5 andD1 receptors, their c-terminus tails have little similarity.[12]
In humans, D5 receptor is encoded on thechromosome 4p15.1–p15.3.[13] The gene lacks introns[9] and encodes a product of 477amino acids.[6] Two pseudogenes for D5 receptor exist that share 98% sequence with each other and 95% sequence with the functional DRD5 gene. These genes contain severalin-framestop codons that prevent these genes from transcribing a functional protein.[9]
D5 receptor participates in the synaptic processes that underlie learning and memory. These receptors participate in the formation ofLTD in rodentstriatum, which is opposite to theD1 receptor involvement with the formation ofLTP in the same brain region.[21] D5 receptors are also associated with the consolidation of fear memories inamygdala. It has been shown thatM1-Muscarinic receptors cooperate with D5 receptors andbeta-2 adrenergic receptors toconsolidate cued fear memory. It is suggested that theseG protein-coupled receptors redundantly activatephospholipase C inbasolateral amygdala. One effect of the activation of phospholipase C is deactivation ofKCNQ channels.[22] Since KCNQ channels conductM current that raises the threshold foraction potential,[23] deactivation of these channels leads to increased neuronal excitability and enhanced memory consolidation.[22]
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 ahaplotype of DRD5 that is protective against initiation of smoking.[25]
Dinucleotide repeats of DRD5 gene are associated withADHD in humans. 136-bp allele of the gene was shown to be a protective factor against developing this disorder, and 148-bp allele of DRD5 was shown to be arisk factor for it.[14] There exist two types of the 148-bp allele of DRD5, a long and a short one. The short dinucleotide repeat allele is associated with ADHD, but not the long one.[26] Another allele of DRD5 that is moderately associated with ADHD susceptibility is 150 bp.[27]In arat model of ADHD, low density of D5 was found in thehippocampalpyramidal cellsomas. Deficiency in D5 receptors may contribute tolearning problems that may be associated with ADHD.[28]
D5 receptors may be involved inburst firing ofsubthalamic nucleus neurons in6-OHDA rat model ofParkinson's disease. In this animal model, blockage of D5 receptors withflupentixol reduces burst firing and improves motor deficits.[29] 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.[30][31]
Several polymorphisms in DRD5 genes have been associated with susceptibility toschizophrenia. The 148 bp allele of DRD5 was linked to increased risk of schizophrenia.[32] Somesingle-nucleotide polymorphisms in this gene, including changes in rs77434921, rs1800762, rs77434921, and rs1800762, in northernHan Chinese population.[33]
D5 receptor is believed to participate in modulation ofpsychostimulant-inducedlocomotion. Mice lacking D5 receptors show increased motor response to administration ofmethamphetamine thanwild type mice,[34] which suggests that these receptors have a role in controlling motor activity.
D5 receptor may be involved in modulation of the neuronal pathways that regulateblood pressure. Mice lacking this receptor in their brains showedhypertension and elevatedblood pressure, which may have been caused by increasedsympathetic tone.[35] D5 receptors that are expressed in kidneys are also involved in the regulation of blood pressure via modulating expression ofrenalase and excretion ofsodium, and disturbance of these processes can contribute to hypertension as well.[20]
D5 receptors negatively regulate production ofIFNγ byNK cells. The expression of D5 receptors was shown to be upregulated in NK cells in response to prolonged stimulation withrecombinantinterleukin 2. This upregulation inhibitsproliferation of the NK cells and suppresses synthesis of IFNγ. Activation of D5 prevents p50, part ofNF-κB protein complex, fromrepressing the transcription ofmiRNA 29a. Because miRNA29a targetsmRNA of IFNγ, the expression of IFNγ protein is diminished.[36]
D5 receptors are involved in activation and differentiation ofT helper 17 cells. Specifically, these receptors play a role in polarization ofCD4+ T-cells into the T helper 17 cells by modulating secretion ofinterleukin 12 andinterleukin 23 in response to stimulation withLPS.[37]
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.[11]
D5 receptor has been shown to formheteromers withD2 receptors. Co-activation of these receptors within the heteromer triggers increase inintracellular calcium. This calcium signaling is dependent onGq-11 protein signaling andphospholipase C, as well as on the influx of extracellularcalcium.[41] Heteromers between D2 and D5 receptors are formed by adjacentarginines in ic3 (third cytoplasmic loop[42]) of D2 receptor and three adjacentc-terminusglutamic acids in D5 receptor. Heteromerization of2 and D5 receptors can be disrupted through changes of single amino acids in thec-terminus of the D5 receptor.[12]
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.[44] However, expression of D5 receptors has been assessed usingimmunohistochemistry. In this technique, twopeptides were obtained from third extracellular loop and third intracellular loop of the receptor, andantisera were developed for staining the receptor in frozenmouse brain tissue.[35] A method involvingmRNA probes forin situ hybridization has been developed, which allowed to separately examine the expression of D1 and D5 receptors in the mouse brain.[24]
DRD5knockout mice can be obtained by crossing 129/SvJ1 andC57BL/6J mice.[10] D5 receptor can also be inactivated in ananimal model by flanking the DRD5 gene withloxP site, allowing to generate tissue or animal lacking functional D5 receptors.[45] The expression of D5 receptorin vitro can also be silenced usingantisense oligonucleotides.[20]
^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.Bibcode:1991Natur.350..614S.doi:10.1038/350614a0.PMID1826762.S2CID4373022.
^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.S2CID34954571.
^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.hdl:10533/144001.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.S2CID7548859.
^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.S2CID25731931.
^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.S2CID43454552.
^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.S2CID44740438.
^Muir WJ, Thomson ML, McKeon P, Mynett-Johnson L, Whitton C, Evans KL, Porteous DJ, Blackwood DH (2001). "Markers close to the dopamine D5 receptor gene (DRD5) show significant association with schizophrenia but not bipolar disorder".American Journal of Medical Genetics.105 (2):152–8.doi:10.1002/1096-8628(2001)9999:9999<::AID-AJMG1163>3.0.CO;2-2.PMID11304828.
^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.
^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.S2CID11317445.
Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998). "Dopamine receptors: from structure to function".Physiol. Rev.78 (1):189–225.doi:10.1152/physrev.1998.78.1.189.PMID9457173.
Grandy DK, Allen LJ, Zhang Y, Magenis RE, Civelli O (1992). "Chromosomal localization of three human D5 dopamine receptor genes".Genomics.13 (4):968–973.doi:10.1016/0888-7543(92)90009-H.PMID1387108.
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.Bibcode:1991Natur.350..614S.doi:10.1038/350614a0.PMID1826762.S2CID4373022.
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.S2CID195213008.
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.S2CID33503277.
"Dopamine Receptors: D1".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 31 December 2014. Retrieved4 December 2008.
