Alternative titles; symbols
HGNC Approved Gene Symbol: OPRD1
Cytogenetic location: 1p35.3 Genomic coordinates (GRCh38): 1:28,812,170-28,871,267 (from NCBI)
Bzdega et al. (1993) cloned the mouse Oprd1 gene from a mouse neuroblastoma-rat glioma hybrid cell line. The clone they isolated was apparently identical to those reported by others (e.g., Evans et al., 1992). They found full-length transcripts of the gene in mouse brain but in no other tissues examined. Within the brain the gene was expressed at low levels in many regions, but transcripts were found in particularly large amounts in the anterior pituitary and pineal glands. Since these tissues are located outside the blood-brain barrier, opioid peptides easily can reach receptors in these areas from the blood.
By RT-PCR screening of melanoma cell lines for the presence of delta-opioid receptor mRNA, Mayer et al. (2000) detected a 623-bp product in addition to the expected 773-bp product. Ligand binding studies confirmed the presence of the delta-opioid receptors on pigment cells at the expected binding capacity but at somewhat lower density than expected. Further RT-PCR screening determined that the normal receptor is present on all normal and malignant pigment and neuronal cells, whereas the short form is found exclusively in the tumors. Sequence analysis indicated that the short receptor is not encoded by the genome but results from mRNA processing and a deletion, apparently by a transposon mechanism, of 144 bp within the third exon. This region corresponds to the third cytoplasmic domain of the receptor molecule.
Mayer et al. (2000) noted that the OPRD1 gene contains 3 exons.
Bzdega et al. (1993) mapped the mouse Oprd1 gene, which they called Nbor for 'neuroblastoma opiate receptor,' to the distal region of mouse chromosome 4 by linkage studies. It was found to lie between Lck and Gnb-1. The human homologs of these 2 genes, LCK (153390) and GNB1 (139380), are located on human chromosome 1p; thus, the human gene for delta-opiate receptor is probably in this region. (GNB1 is mapped to 1pter-p31.2; LCK is mapped to 1p35-p32.)
Kaufman et al. (1994) reported linkage relationships of Oprd1 on mouse chromosome 4 and stated that the human homolog had been mapped to 1p by in situ hybridization.
Befort et al. (1994) assigned the OPRD1 gene to chromosome 1p36.1-p34.3 by isotopic in situ hybridization and the homologous gene to mouse chromosome 4 by the same method.
Jordan and Devi (1999) provided biochemical and pharmacologic evidence for the heterodimerization of 2 fully functional opioid receptors, kappa (OPRK1; 165196) and delta. This results in a new receptor that exhibits ligand binding and functional properties that are distinct from those of either receptor. Furthermore, the kappa-delta heterodimer synergistically binds highly selective agonists and potentiates signal transduction.
Whistler et al. (2002) identified a G protein-coupled receptor-associated sorting protein, GASP (300417), that interacts with the cytoplasmic tail of OPRD1 and appears to modulate OPRD1 recycling and trafficking to lysosomes. Opioid peptide activation of HEK293 cells transfected with GASP resulted in rapid endocytosis and proteolysis of OPRD1. Using several binding assays with truncated GASP proteins, Whistler et al. (2002) determined that the C-terminal portion of GASP binds specifically to the OPRD1 tail.
Agirregoitia et al. (2006) studied the expression and localization of delta (OPRD1), kappa (OPRK1), and mu (OPRM1; 600018) opioid receptors on human spermatozoa and the implication in sperm motility. These receptors are located in different parts of the head, in the middle region, and in the tail of the sperm. Progressive motility of spermatozoa, an important parameter to evaluate male fertility, was significantly reduced after incubation with the mu receptor agonist morphine, whereas this effect was antagonized in the presence of the corresponding antagonist naloxone. The delta receptor antagonist naltrindole significantly reduced progressive motility immediately after its addition. However, the delta receptor agonist DPDPE had no significant effect. Finally, neither the kappa receptor agonist U50488 nor its antagonist norbinaltorphimine significantly affected the progressive motility of human spermatozoa.
Pharmacologic and electrophysiologic evidence indicates that opioid receptors are involved in the mechanism of heroin dependence. Thus, opioid receptors are appropriate candidate genes for case-control association studies of heroin dependence. To test the hypothesis that OPRD1 or a closely linked gene is associated with heroin dependence, Xu et al. (2002) used 5-prime nuclease assays to genotype 2 OPRD1 SNPs in 450 Chinese heroin dependent patients and 304 unaffected controls from the same population. In addition, 5 SNPs distributed in 4 other genes (ADH1B, 103720; ALDH2, 100650; OPRM1, 600018; and DRD1, 126449) were used as genomic control loci to test the case and control populations for stratification bias. One of the SNPs, 80G, was absent from both Chinese opioid dependence patients and controls; genotype and allele frequencies at the other OPRD1 SNP, 921T-C, were not significantly different.
Zhang et al. (2008) genotyped 11 SNPs in the OPRD1 gene in spanning OPRD1 were examined in 1,063 European Americans, including 620 with substance dependence, 557 with alcohol dependence (103780), 225 with cocaine dependence, 111 with opioid dependence (610064), and 443 controls. Although individual SNPs in general did not show significant associations after multiple corrections, haplotype analyses showed that a 6-SNP haplotype, which harbors the G allele of 80G-T (rs1042114) and the C allele of 921C-T (rs2234918), was significantly associated with alcohol dependence (p = 0.002) and opioid dependence (p less than 0.001). This haplotype yielded odds ratios of 6.43 for alcohol dependence and 50.57 for opioid dependence.
Crystal Structure
Granier et al. (2012) reported the crystal structure of the mouse delta-opioid receptor bound to the subtype-selective antagonist naltrindole. Together with the structures of the mu-opioid receptor and kappa-opioid receptor, the delta-opioid receptor structure provided insights into conserved elements of opioid ligand recognition while also revealing structural features associated with ligand subtype selectivity. The binding pocket of opioid receptors can be divided into 2 distinct regions. Whereas the lower part of this pocket is highly conserved among opioid receptors, the upper part contains divergent residues that confer subtype selectivity. This provides a structural explanation and validation for the 'message-address' model of opioid receptor pharmacology, in which distinct 'message' (efficacy) and 'address' (selectivity) determinants are contained within a single ligand. Comparison of the address region of the delta-opioid receptor with other G protein-coupled receptors (GPCRs) revealed that this structural organization may be a more general phenomenon, extending to other GPCR families as well.
Fenalti et al. (2014) presented the 1.8-angstrom high-resolution crystal structure of the human delta-opioid receptor, revealing the presence and fundamental role of a sodium ion in mediating allosteric control of receptor functional selectivity and constitutive activity. The distinctive delta-opioid receptor sodium ion site architecture is centrally located in a polar interaction network in the 7-transmembrane bundle core, with the sodium ion stabilizing a reduced agonist affinity state, and thereby modulating signal transduction. Site-directed mutagenesis and functional studies revealed that changing the allosteric sodium site residue asn13 to alanine or valine augments constitutive beta-arrestin-mediated signaling (see 107940). Asp95-to-ala, asn310-to-ala, and asn314-to-ala mutations transformed classical delta-opioid antagonists such as naltrindole into potent beta-arrestin-biased agonists. Fenalti et al. (2014) concluded that their data established the molecular basis for allosteric sodium ion control in opioid signaling, revealing that sodium-coordinating residues act as 'efficacy switches' at a prototypic G protein-coupled receptor.
Filliol et al. (2000) generated Oprd1-deficient mice and compared the behavioral responses of mice lacking Oprd1, Oprm, and Oprk1 in several models of anxiety and depression. Their data showed no detectable phenotype in Oprk1 -/- mutants, suggesting that kappa-receptors do not have a role in this aspect of opioid function. Opposing phenotypes in Oprm -/- and Oprd1 -/- mutants contrasted with the classic notion of similar activities of mu- and delta-receptors. Anxiogenic- and depressive-like responses in Oprd1 -/- mice indicated that delta-receptor activity contributes to improvement of mood states. Filliol et al. (2000) concluded that the Oprd1-encoded receptor, which has been proposed to be a promising target for the clinical management of pain, should also be considered in the treatment of drug addiction and other mood-related disorders.
Agirregoitia, E., Valdivia, A., Carracedo, A., Casis, L., Gil, J., Subiran, N., Ochoa, C., Irazusta, J. Expression and localization of delta-, kappa-, and mu-opioid receptors in human spermatozoa and implications for sperm motility. J. Clin. Endocr. Metab. 91: 4969-4975, 2006. [PubMed: 16984994] [Full Text: https://doi.org/10.1210/jc.2006-0599]
Befort, K., Mattei, M.-G., Roeckel, N., Kieffer, B. Chromosomal localization of the delta opioid receptor gene to human 1p34.3-p36.1 and mouse 4D bands by in situ hybridization. Genomics 20: 143-145, 1994. [PubMed: 8020949] [Full Text: https://doi.org/10.1006/geno.1994.1146]
Bzdega, T., Chin, H., Kim, H., Jung, H. H., Kozak, C. A., Klee, W. A. Regional expression and chromosomal localization of the delta opiate receptor gene. Proc. Nat. Acad. Sci. 90: 9305-9309, 1993. [PubMed: 8415697] [Full Text: https://doi.org/10.1073/pnas.90.20.9305]
Evans, C. J., Keith, D. E., Morrison, H., Magendzo, K., Edwards, R. H. Cloning of a delta opioid receptor by functional expression. Science 258: 1952-1955, 1992. [PubMed: 1335167] [Full Text: https://doi.org/10.1126/science.1335167]
Fenalti, G., Giguere, P. M., Katritch, V., Huang, X.-P., Thompson, A. A., Cherezov, V., Roth, B. L., Stevens, R. C. Molecular control of delta-opioid receptor signaling. Nature 506: 191-196, 2014. [PubMed: 24413399] [Full Text: https://doi.org/10.1038/nature12944]
Filliol, D., Ghozland, S., Chluba, J., Martin, M., Matthes, H. W. D., Simonin, F., Befort, K., Gaveriaux-Ruff, C., Dierich, A., LeMeur, M., Valverde, O., Maldonado, R., Kieffer, B. L. Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses. Nature Genet. 25: 195-200, 2000. [PubMed: 10835636] [Full Text: https://doi.org/10.1038/76061]
Granier, S., Manglik, A., Kruse, A. C., Kobilka, T. S., Thian, F. S., Weis, W. I., Kobilka, B. K. Structure of the delta-opioid receptor bound to naltrindole. Nature 485: 400-404, 2012. [PubMed: 22596164] [Full Text: https://doi.org/10.1038/nature11111]
Jordan, B. A., Devi, L. A. G-protein-coupled receptor heterodimerization modulates receptor function. Nature 399: 697-700, 1999. [PubMed: 10385123] [Full Text: https://doi.org/10.1038/21441]
Kaufman, D. L., Xia, Y.-R., Keith, D. E., Jr., Newman, D., Evans, C. J., Lusis, A. J. Localization of the delta-opioid receptor gene to mouse chromosome 4 by linkage analysis. Genomics 19: 405-406, 1994. [PubMed: 8188281] [Full Text: https://doi.org/10.1006/geno.1994.1087]
Mayer, P., Tischmeyer, H., Jayasinghe, M., Bonnekoh, B., Gollnick, H., Teschemacher, H., Hollt, V. A delta-opioid receptor lacking the third cytoplasmic loop is generated by atypical mRNA processing in human malignomas. FEBS Lett. 480: 156-160, 2000. [PubMed: 11034319] [Full Text: https://doi.org/10.1016/s0014-5793(00)01929-3]
Whistler, J. L., Enquist, J., Marley, A., Fong, J., Gladher, F., Tsuruda, P., Murray, S. R., von Zastrow, M. Modulation of postendocytic sorting of G protein-coupled receptors. Science 297: 615-620, 2002. [PubMed: 12142540] [Full Text: https://doi.org/10.1126/science.1073308]
Xu, K., Liu, X., Nagarajan, S., Gu, X.-Y., Goldman, D. Relationship of the delta-opioid receptor gene to heroin abuse in a large Chinese case/control sample. Am. J. Med. Genet. 110: 45-50, 2002. [PubMed: 12116270] [Full Text: https://doi.org/10.1002/ajmg.10374]
Zhang, H., Kranzler, H. R., Yang, B.-Z., Luo, X., Gelernter, J. The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk. Molec. Psychiat. 13: 531-543, 2008. [PubMed: 17622222] [Full Text: https://doi.org/10.1038/sj.mp.4002035]