Alternative titles; symbols
HGNC Approved Gene Symbol: DRD1
Cytogenetic location: 5q35.2 Genomic coordinates (GRCh38): 5:175,440,036-175,444,182 (from NCBI)
The diverse physiologic actions of dopamine are mediated by its interaction with 2 types of G protein-coupled receptor, D1 and D2 (126450), which stimulate and inhibit, respectively, the enzyme adenylyl cyclase.
Three groups reported the cloning of the D1 dopamine receptor gene (Dearry et al., 1990; Zhou et al., 1990; Sunahara et al., 1990). The gene encodes a protein of 446 amino acids having a predicted relative molecular mass of 49,300 and a transmembrane topology similar to that of other G protein-coupled receptors. Northern blot analysis and in situ hybridization showed that the mRNA for this receptor is most abundant in caudate, nucleus accumbens, and olfactory tubercle, with little or no mRNA detectable in substantia nigra, liver, kidney, or heart (Dearry et al., 1990).
The activator region-1 (AR1) in the upstream promoter of the D1A gene contains partially overlapping binding sites for SP1 (189906) and AP2 (see TFAP2A; 107580) on opposite strands. Using gel mobility shift and reporter gene assays, Yang et al. (2000) found that human ZIC2 (603073) bound the AR1 sequence and repressed its expression. ZIC2 also significantly decreased expression of endogenous D1a in a mouse neuroblastoma cell line. ZIC2 efficiently blocked SP1 and SP3 (601804) binding to an AR1 probe and inhibited SP1- and SP3-mediated AR1 promoter activity. ZIC2 also displaced SP1 and SP2 binding to AR1 over time, leading to complete suppression of D1A promoter activity.
A critical step in transport of membrane proteins from the endoplasmic reticulum (ER) to the cell surface involves bulk flow mechanisms or the presence of specific ER-export sequences. Bermak et al. (2001) noted the presence of a conserved 4-amino acid spacing of hydrophobic residues, FxxxFxxxF, within the proximal C terminus of GPCRs, including DRD1. Fluorescence microscopy analysis of rat Drd1 with its C-terminal phe residues mutated to ala demonstrated that the phe residues are critical to cell surface localization. Functional analysis showed reduced ligand binding and ablated cAMP production in response to dopamine in cells expressing the mutant Drd1 protein. Expression of a wildtype C-terminal Drd1/N-terminal CD8 (186910) chimeric protein, but not of a phe-mutant Drd1 protein, conferred cell surface expression. Bermak et al. (2001) concluded that the FxxxFxxxF motif and all of its phe residues are essential for normal receptor transport.
Using a yeast 2-hybrid screen, Bermak et al. (2001) identified DRIP78 (606092) as a protein that interacts with DRD1. Binding analysis showed that the hydrophobic sequence of rat Drd1 is critical for its interaction with Drip78, and that residues 488 to 673 of rat Drip78 contain 2 potential zinc-finger domains that are crucial for its association with Drd1. Coexpression of Drd1 and Drip78 resulted in inhibition of Drd1 surface expression and intracellular trapping. Bermak et al. (2001) concluded that DRIP78, like calnexin (CANX; 114217) and GRP78 (HSPA5; 138120), is an ER-resident protein that prevents premature transport of protein cargo to the Golgi by masking the FxxxFxxxF motif of DRD1.
By immunohistochemical analysis, Mayerhofer et al. (1999) showed that DRD1 is expressed in human ovarian tissue within granulosa cells of large follicles and in luteal cells of the corpus luteum. In granulosa luteal cells, DRD1 immunoreactivity was associated with the cell membrane and/or with the cytoplasm of most cells. DRD1 in granulosa cell (GC) cultures was biologically active. Treatment of human luteinized GC cultures with SKF38393, a selective dopamine receptor agonist, increased cAMP levels 2- to 3-fold within 3 to 6 hours. SKF38393 treatment also significantly increased the threonine phosphorylation of DARPP32 (604399).
Lee et al. (2002) reported that dopamine D1 receptors modulate NMDA glutamate receptor-mediated functions through direct protein-protein interactions. Two regions in the D1 receptor carboxyl tail could directly and selectively couple to NMDA glutamate receptor subunits NR1-1A (138249) and NR2A (138253). While one interaction was involved in the inhibition of NMDA receptor-gated currents, the other was implicated in the attenuation of NMDA receptor-mediated excitotoxicity through a phosphatidylinositol 3-kinase (see 171833)-dependent pathway.
Stipanovich et al. (2008) demonstrated that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kD dopamine- and cAMP-regulated phosphoprotein (DARPP32; 604399). This accumulation is mediated through a signaling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A (see 176915), and dephosphorylation of DARPP32 at ser97 and inhibition of its nuclear export. The nuclear accumulation of DARPP32, a potent inhibitor of protein phosphatase-1 (see 176875), increased the phosphorylation of histone H3 (see 602810), an important component of nucleosomal response. Mutation of ser97 profoundly altered behavioral effects of drugs of abuse and decreased motivation for food, underlining the functional importance of this signaling cascade.
Working memory is a key function for human cognition, dependent on adequate dopamine neurotransmission. McNab et al. (2009) showed that the training of working memory, which improves working memory capacity, is associated with changes in the density of cortical dopamine D1 receptors. Fourteen hours of training over 5 weeks in 13 volunteers, healthy males aged 20 to 28 years, was associated with changes in both prefrontal and parietal D1 binding potential, as determined by positron emission tomography while the participants were resting before and after training. McNab et al. (2009) concluded that this plasticity of the dopamine D1 receptor system demonstrates a reciprocal interplay between mental activity and brain biochemistry in vivo.
Lim et al. (2012) showed that chronic stress in mice decreases the strength of excitatory synapses on D1 dopamine receptor-expressing nucleus accumbens medium spiny neurons owing to activation of the melanocortin-4 receptor (MC4R; 155541). Stress-elicited increases in behavioral measurements of anhedonia, but not increases in measurements of behavioral despair, are prevented by blocking these melanocortin-4 receptor-mediated synaptic changes in vivo. Lim et al. (2012) concluded that stress-elicited anhedonia requires a neuropeptide-triggered, cell type-specific synaptic adaptation in the nucleus accumbens and that distinct circuit adaptations mediate other major symptoms of stress-elicited depression.
Sunahara et al. (1990) reported that the DRD1 gene is intronless.
By Southern blot hybridization to DNAs from a hybrid cell panel, Sunahara et al. (1990) mapped the DRD1 gene to chromosome 5. Family linkage studies confirmed this assignment and suggested that it is in the same general region as the gene for glucocorticoid receptor (138040) and D5S22, a marker about 12 cM from GRL. This places it in the 5q31-q34 region near the structurally homologous genes for beta-2-adrenergic receptor (109690) and alpha-1-adrenergic receptor (104220). Using pulsed field gel electrophoresis and a range of different restriction enzyme digests, Boultwood et al. (1991) established that GRL and DRD1 are on the same 300-kb genomic DNA fragment. Grandy et al. (1990) used the recently cloned DRD1 gene to map the locus to chromosome 5 in rodent-human somatic cell hybrids. Fluorescence in situ hybridization refined the localization to 5q35.1. A 2-allele EcoRI RFLP associated with DRD1 allowed confirmation of the localization by linkage analysis in CEPH families. The homologous gene in the mouse is located on chromosome 13 (Wilkie et al., 1993).
Association with Systolic Blood Pressure Levels
The distal end of 5q, 5q31.1-qter, contains the genes for 2 adrenergic receptors, ADRB2 (109690) and ADRA1B (104220), and the dopamine receptor type 1A gene. Krushkal et al. (1998) used an efficient discordant sib-pair ascertainment scheme to investigate the impact of this region of the genome on variation in systolic blood pressure in young Caucasians. They measured 8 highly polymorphic markers spanning this positional candidate gene-rich region in 427 individuals from 55 3-generation pedigrees containing 69 discordant sib pairs, and calculated multipoint identity by descent probabilities. The results of genetic linkage and association tests indicated that the region between markers D5S2093 and D5S462 was significantly linked to one or more polymorphic genes influencing interindividual variation in systolic blood pressure levels. Since the ADRA1B and DRD1A genes are located close to these markers, the data suggested that genetic variation in one or both of these G protein-coupled receptors, which participate in the control of vascular tone, plays an important role in influencing interindividual variation in systolic blood pressure levels.
Association with Nicotine Dependence
Huang et al. (2008) found a significant association between nicotine dependence (188890) and a SNP (rs686) in the DRD1 gene among 1,366 African Americans. In a pooled sample of 1,366 African Americans and 671 European Americans, rs686 and rs4532 were both significantly associated with nicotine dependence. Several haplotypes related to these SNPs also suggested an association. In vitro functional expression studies indicated that rs686, which is located in the 3-prime untranslated region, is functionally involved in the regulation of DRD1 expression.
Association with Schizophrenia
Allen et al. (2008) performed a metaanalysis comparing 725 patients with schizophrenia (see 181500) with 1,075 controls and found that the DRD1 -48A-G allele (rs4532) was associated with susceptibility to schizophrenia (odds ratio, 1.18; 95% CI, 1.01-1.38; p = 0.037). According to the Venice guidelines for the assessment of cumulative evidence in genetic association studies (Ioannidis et al., 2008), the DRD1 association showed a 'strong' degree of epidemiologic credibility.
The brain dopaminergic system is a critical modulator of basal ganglion function and plasticity. To investigate the contribution of the dopamine D1 receptor to this modulation, Xu et al. (1994) used gene targeting technology to generate D1 receptor mutant mice. Although histologic analyses suggested no major changes in the anatomy of mutant mouse brains, the expression of dynorphin (131340) was greatly reduced in the striatum and related regions of the basal ganglia. The mutant mice did not respond to the stimulant and suppressive effects of D1 receptor agonists and antagonists, respectively, and they exhibited locomotor hyperactivity.
Since dopamine produced by the kidney is an intrarenal regulator of sodium transport, Albrecht et al. (1996) investigated the possibility that an abnormality of the dopaminergic system may be important in the pathogenesis of hypertension. In the spontaneously hypertensive rat (SHR), in spite of normal renal production of dopamine and normal receptor density, there is defective transduction of the D1 receptor signal in renal proximal tubules, resulting in decreased inhibition of sodium transport by dopamine. Two D1-like receptor genes have been cloned in mammals, DRD1A and DRD1B (126453). Although both receptor genes are expressed in the kidney, DRD1A is more abundant than DRD1B in renal proximal tubules. Therefore, Albrecht et al. (1996) studied the effect of deletion of D1A receptors in mice generated by homologous recombination. They found that systolic blood pressure was greater in homozygous and heterozygous mice than in normal sex-matched litter mate controls; moreover, mice lacking 1 or both Drd1a alleles developed diastolic hypertension.
Chronic blockade of dopamine D2 receptors, a common mechanism of action for antipsychotic drugs, downregulates D1 receptors in the prefrontal cortex and, as shown by Castner et al. (2000), produces severe impairments in working memory. These deficits were reversed in monkeys by short-term coadministration of a D1 agonist, ABT431, and this improvement was sustained for more than a year after cessation of D1 treatment. Castner et al. (2000) concluded that pharmacologic modulation of the D1 signaling pathway can produce long-lasting changes in functional circuits underlying working memory. Resetting this pathway by brief exposure to the agonist may provide a valuable strategy for therapeutic intervention in schizophrenia and other dopamine-dysfunctional states.
Albrecht, F. E., Drago, J., Felder, R. A., Printz, M. P., Eisner, G. M., Robillard, J. E., Sibley, D. R., Westphal, H. J., Jose, P. A. Role of the D-1A dopamine receptor in the pathogenesis of genetic hypertension. J. Clin. Invest. 97: 2283-2288, 1996. Note: Erratum: J. Clin. Invest. 97: following 2925, 1996. [PubMed: 8636408] [Full Text: https://doi.org/10.1172/JCI118670]
Allen, N. C., Bagade, S., McQueen, M. B., Ioannidis, J. P. A., Kavvoura, F. K., Khoury, M. J., Tanzi, R. E., Bertram, L. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nature Genet. 40: 827-834, 2008. [PubMed: 18583979] [Full Text: https://doi.org/10.1038/ng.171]
Bermak, J. C., Li, M., Bullock, C., Zhou, Q.-Y. Regulation of transport of the dopamine D1 receptor by a new membrane-associated ER protein. Nature Cell Biol. 3: 492-498, 2001. [PubMed: 11331877] [Full Text: https://doi.org/10.1038/35074561]
Boultwood, J., Lewis, M. S., Wainscoat, J. S. Physical linkage of glucocorticoid receptor (GRL) and dopamine D1 receptor (DRD1) on the long arm of chromosome 5.(Abstract) Cytogenet. Cell Genet. 58: 1894 only, 1991.
Castner, S. A., Williams, G. V., Goldman-Rakic, P. S. Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation. Science 287: 2020-2022, 2000. [PubMed: 10720329] [Full Text: https://doi.org/10.1126/science.287.5460.2020]
Dearry, A., Gingrich, J. A., Falardeau, P., Fremeau, R. T., Jr., Bates, M. D., Caron, M. G. Molecular cloning and expression of the gene for a human D(1) dopamine receptor. Nature 347: 72-76, 1990. [PubMed: 2144334] [Full Text: https://doi.org/10.1038/347072a0]
Grandy, D. K., Zhou, Q.-Y., Allen, L., Litt, R., Magenis, R. E., Civelli, O., Litt, M. A human D(1) dopamine receptor gene is located on chromosome 5 at q35.1 and identifies an EcoRI RFLP. Am. J. Hum. Genet. 47: 828-834, 1990. [PubMed: 1977312]
Huang, W., Ma, J. Z., Payne, T. J., Beuten, J., Dupont, R. T., Li, M. D. Significant association of DRD1 with nicotine dependence. Hum. Genet. 123: 133-140, 2008. [PubMed: 18092181] [Full Text: https://doi.org/10.1007/s00439-007-0453-9]
Ioannidis, J. P., Boffetta, P., Little, J., O'Brien, T. R., Uitterlinden, A. G., Vineis, P., Balding, D. J., Chokkalingam, A., Dolan, S. M., Flanders, W. D., Higgins, J. P., McCarthy, M. I., McDermott, D. H., Page, G. P., Rebbeck, T. R., Seminara, D., Khoury, M. J. Assessment of cumulative evidence on genetic associations: interim guidelines. Int. J. Epidemiol. 37: 120-132, 2008. [PubMed: 17898028] [Full Text: https://doi.org/10.1093/ije/dym159]
Krushkal, J., Xiong, M., Ferrell, R., Sing, C. F., Turner, S. T., Boerwinkle, E. Linkage and association of adrenergic and dopamine receptor genes in the distal portion of the long arm of chromosome 5 with systolic blood pressure variation. Hum. Molec. Genet. 7: 1379-1383, 1998. [PubMed: 9700190] [Full Text: https://doi.org/10.1093/hmg/7.9.1379]
Lee, F. J. S., Xue, S., Pei, L., Vukusic, B., Chery, N., Wang, Y., Wang, Y. T., Niznik, H. B., Yu, X., Liu, F. Dual recognition of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor. Cell 111: 219-230, 2002. [PubMed: 12408866] [Full Text: https://doi.org/10.1016/s0092-8674(02)00962-5]
Lim, B. K., Huang, K. W., Grueter, B. A., Rothwell, P. E., Malenka, R. C. Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 487: 183-189, 2012. [PubMed: 22785313] [Full Text: https://doi.org/10.1038/nature11160]
Mayerhofer, A., Hemmings, H. C., Jr., Snyder, G. L., Greengard, P., Boddien, S., Berg, U., Brucker, C. Functional dopamine-1 receptors and DARPP-32 are expressed in human ovary and granulosa luteal cells in vitro. J. Clin. Endocr. Metab. 84: 257-264, 1999. [PubMed: 9920093] [Full Text: https://doi.org/10.1210/jcem.84.1.5378]
McNab, F., Varrone, A., Farde, L., Jucaite, A., Bystritsky, P., Forssberg, H., Klingberg, T. Changes in cortical dopamine D1 receptor binding associated with cognitive training. Science 323: 800-802, 2009. [PubMed: 19197069] [Full Text: https://doi.org/10.1126/science.1166102]
Stipanovich, A., Valjent, E., Matamales, M., Nishi, A., Ahn, J.-H., Maroteaux, M., Bertran-Gonzalez, J., Brami-Cherrier, K., Enslen, H., Corbille, A.-G., Filhol, O., Nairn, A. C., Greengard, P., Herve, D., Girault, J.-A. A phosphatase cascade by which rewarding stimuli control nucleosomal response. Nature 453: 879-884, 2008. [PubMed: 18496528] [Full Text: https://doi.org/10.1038/nature06994]
Sunahara, R. K., Niznik, H. B., Weiner, D. M., Stormann, T. M., Brann, M. R., Kennedy, J. L., Gelernter, J. E., Rozmahel, R., Yang, Y., Israel, Y., Seeman, P., O'Dowd, B. F. Human dopamine D1 receptor encoded by an intronless gene on chromosome 5. Nature 347: 80-83, 1990. [PubMed: 1975640] [Full Text: https://doi.org/10.1038/347080a0]
Wilkie, T. M., Chen, Y., Gilbert, D. J., Moore, K. J., Yu, L., Simon, M. I., Copeland, N. G., Jenkins, N. A. Identification, chromosomal location, and genome organization of mammalian G-protein-coupled receptors. Genomics 18: 175-184, 1993. [PubMed: 8288218] [Full Text: https://doi.org/10.1006/geno.1993.1452]
Xu, M., Moratalla, R., Gold, L. H., Hiroi, N., Koob, G. F., Graybiel, A. M., Tonegawa, S. Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses. Cell 79: 729-742, 1994. [PubMed: 7954836] [Full Text: https://doi.org/10.1016/0092-8674(94)90557-6]
Yang, Y., Hwang, C. K., Junn, E., Lee, G., Mouradian, M. M. ZIC2 and Sp3 repress Sp1-induced activation of the human D(1A) dopamine receptor gene. J. Biol. Chem. 275: 38863-38869, 2000. [PubMed: 10984499] [Full Text: https://doi.org/10.1074/jbc.M007906200]
Zhou, Q.-Y., Grandy, D. K., Thambi, L., Kushner, J. A., Van Tol, H. H. M., Cone, R., Pribnow, D., Salon, J., Bunzow, J. R., Civelli, O. Cloning and expression of human and rat D(1) dopamine receptors. Nature 347: 76-80, 1990. [PubMed: 2168520] [Full Text: https://doi.org/10.1038/347076a0]