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Gene Review

DIO3  -  deiodinase, iodothyronine, type III

Homo sapiens

Synonyms: 5DIII, D3, DIOIII, ITDI3, TXDI3, ...
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Disease relevance of DIO3

  • D3 activity and mRNA was found in ECC-1 endometrium carcinoma cells, MCF-7 mammacarcinoma cells, WRL-68 embryonic liver cells, and SH-SY5Y neuroblastoma cells, but not in the HepG2 hepatocarcinoma cell line or in any choriocarcinoma or astrocytoma cell line [1].
  • In vivo, all antagonists except GR 103,691 prevented the induction of hypothermia by (+)-PD 128,907 (0.63 mg/kg s.c.) and a further preferential D3 agonist, (+)-7-OH-DPAT (0.16 mg/kg s.c.). On the other hand, haloperidol, (+)-AJ 76, (+)-UH 232 and nafadotride all induced catalepsy in rats, whereas (+)-S 14297, U 99194 and GR 103,691 were inactive [2].
  • The extracellular location of D3 gives ready access to circulating thyroid hormones, explaining its capacity for rapid inactivation of circulating thyroxine and triiodothyronine in patients with hemangiomas and its blockade of the access of maternal thyroid hormones to the human fetus [3].
  • D3 activity in the normal uteroplacental unit regulates the transfer of maternal thyroid hormone to the fetus and, in patients with consumptive hypothyroidism, the rapid destruction of circulating thyroid hormone by tumoral D3 can produce severe hypothyroxinemia [4].
  • These data have led to the categorization of D3 as an oncofetal protein, but recent data indicate that postnatal expression can be reactivated in normal tissues during critical illness and other pathologic conditions [4].

Psychiatry related information on DIO3

  • This review considers the roles that the three deiodinases, types 1, 2 and 3 (D1, D2, and D3), play in regulating intracellular levels of TH during this critical period [5].
  • This finding led to the postulate that D3 receptors may be involved in drug dependence and addiction [6].
  • We compared the frequency of polymorphisms in the dopamine D2 and D3 receptor genes between patients with drug-induced hallucinations and non-hallucinating patients [7].
  • Among the dopamine receptors, D3 can be considered as particularly related to affective disorders due to its neuroanatomical localization in the limbic region of the brain and its relation to the serotoninergic activity of the CNS [8].
  • We hypothesized that individual differences in D3 receptor expression could contribute to individual differences in the locomotor response to novelty in the HR/LR model [9].

High impact information on DIO3

  • The D4 receptor gene has high homology to the human dopamine D2 and D3 receptor genes [10].
  • The goal of this review is to place the exciting advances that have occurred in our understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context [11].
  • We discuss the pathological role of D3 overexpression causing "consumptive hypothyroidism" as well as our current understanding of the pathophysiology of iodothyronine deiodination during illness and amiodarone therapy [11].
  • Type 3 iodothyronine deiodinase (D3) catalyzes the conversion of T4 and T3 to inactive metabolites [12].
  • The D3 selenocysteine insertion sequence element is more potent than that in the type 1 deiodinase or glutathione peroxidase gene, suggesting a high priority for selenocysteine incorporation into this enzyme [12].

Chemical compound and disease context of DIO3


Biological context of DIO3


Anatomical context of DIO3

  • Regulation of Type III Iodothyronine Deiodinase Expression in Human Cell Lines [1].
  • Our data suggest that estradiol may be one of the factors contributing to the induction of D3 activity in the pregnant uterus and that in addition to gene-specific regulatory elements, more distant common regulatory elements also may be involved in the regulation of D3 expression [1].
  • The human DIO3 gene and its mouse homolog, Dio3, map to chromosomes 14q32 and 12F1, respectively, and code for the type 3 deiodinase, an enzyme that inactivates thyroid hormones and is highly expressed during pregnancy and development [19].
  • At rat striatal membranes, dopamine stimulated [35S]GTPgammaS binding by 1.9-fold over basal, but its actions were only partially reversed by the selective D2/D3 receptor antagonist, raclopride, indicating the involvement of other receptor subtypes [20].
  • Exposing cells to a weak base such as primaquine increases the pool of internalized D3, suggesting that D3 is recycled between plasma membrane and early endosomes [3].

Associations of DIO3 with chemical compounds

  • D3 expression in the different cells was not affected by cAMP or thyroid hormone [1].
  • Dexamethasone decreased D3 activity in WRL-68 cells only in the absence of fetal calf serum [1].
  • Estradiol increased D3 activity 3-fold in ECC-1, but not in any other cells [1].
  • Clozapine was, similarly, weakly active in these models, whereas haloperidol, in line with its higher affinity at D2 (and D3) receptors, was potently active [21].
  • In contrast, raclopride displayed low affinity at hD4 (> 3000 nM) vs. hD2 (1.1 nM) and hD3 receptors (1.4 nM) [22].

Regulatory relationships of DIO3

  • TGF-beta induces endogenous D3 in diverse human cell types, including fetal and adult fibroblasts from several tissues, hemangioma cells, fetal epithelia, and skeletal muscle myoblasts [23].
  • Short-term cultures of primary human T cells were used to show that expression of cyclins D2 and D3 is regulated by IL-2 in a concentration- and time-dependent manner [24].

Other interactions of DIO3

  • We examined the activity of the different deiodinases in human cell lines and investigated the regulation of D3 activity and mRNA expression in these cell lines, as well as its possible coexpression with neighboring genes Dlk1 and Dio3os, which may also be especially important during development [1].
  • The rank order of preference (Ki ratio, D2:D3) for D3 receptors (labeled by [3H]-PD 128,907) vs. D2 sites (labeled by [125I]-iodosulpride) was (+)-S 14297 (61) approximately GR 103,691 (60) > U 99194 (14) > nafadotride (9) approximately (+)-UH 232 (8) approximately (+)-AJ 76 (6) > haloperidol (0.2) [2].
  • We analyzed the human DIO3 genomic region and identified a gene (DIO3OS) that is transcribed in the antisense orientation [19].
  • Activation of D3 and/or 5-HT1A receptors may thus contribute to its potential antidepressant properties [25].
  • The present study addressed these issues employing the dopaminergic agonist, quinelorane, which efficaciously stimulated G-protein activation (as assessed by [35S]GTPgammaS binding) at cloned hD2 (and hD3) receptors [20].

Analytical, diagnostic and therapeutic context of DIO3

  • Semiquantitative immunoblotting of homogenates with a D3 antiserum revealed that about 50-fold higher amounts of D3Cys and D3Ala protein are expressed relative to D3wt protein [17].
  • Moreover, D3 fMRI activation in both the contralateral SI and motor cortex correlated positively with the D3 sensory conduction latency [26].
  • D3 mRNA was, however, detectable by RT-PCR, but only at low levels that could not be detected by Northern blots of PBL total RNA [27].
  • The assays were validated by high performance liquid chromatography of the products, and kinetic analysis [Michaelis-Menten constant (Km) of rT3 for D1: 0.5 microM; Km of T3 for D3: 2 nM] [28].
  • Liver D1 is down-regulated and D3 (which is not present in liver and skeletal muscle of healthy individuals) is induced, particularly in disease states associated with poor tissue perfusion [29].


  1. Regulation of Type III Iodothyronine Deiodinase Expression in Human Cell Lines. Kester, M.H., Kuiper, G.G., Versteeg, R., Visser, T.J. Endocrinology (2006) [Pubmed]
  2. A comparative in vitro and in vivo pharmacological characterization of the novel dopamine D3 receptor antagonists (+)-S 14297, nafadotride, GR 103,691 and U 99194. Audinot, V., Newman-Tancredi, A., Gobert, A., Rivet, J.M., Brocco, M., Lejeune, F., Gluck, L., Desposte, I., Bervoets, K., Dekeyne, A., Millan, M.J. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  3. Human type 3 iodothyronine selenodeiodinase is located in the plasma membrane and undergoes rapid internalization to endosomes. Baqui, M., Botero, D., Gereben, B., Curcio, C., Harney, J.W., Salvatore, D., Sorimachi, K., Larsen, P.R., Bianco, A.C. J. Biol. Chem. (2003) [Pubmed]
  4. Physiology and pathophysiology of type 3 deiodinase in humans. Huang, S.A. Thyroid (2005) [Pubmed]
  5. The roles of the iodothyronine deiodinases in mammalian development. Galton, V.A. Thyroid (2005) [Pubmed]
  6. The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence. Heidbreder, C.A., Gardner, E.L., Xi, Z.X., Thanos, P.K., Mugnaini, M., Hagan, J.J., Ashby, C.R. Brain Res. Brain Res. Rev. (2005) [Pubmed]
  7. Association study of dopamine receptor gene polymorphisms with drug-induced hallucinations in patients with idiopathic Parkinson's disease. Makoff, A.J., Graham, J.M., Arranz, M.J., Forsyth, J., Li, T., Aitchison, K.J., Shaikh, S., Grünewald, R.A. Pharmacogenetics (2000) [Pubmed]
  8. Association between the dopamine D3 receptor gene locus (DRD3) and unipolar affective disorder. Dikeos, D.G., Papadimitriou, G.N., Avramopoulos, D., Karadima, G., Daskalopoulou, E.G., Souery, D., Mendlewicz, J., Vassilopoulos, D., Stefanis, C.N. Psychiatr. Genet. (1999) [Pubmed]
  9. Relative expression of D3 dopamine receptor and alternative splice variant D3nf mRNA in high and low responders to novelty. Pritchard, L.M., Logue, A.D., Taylor, B.C., Ahlbrand, R., Welge, J.A., Tang, Y., Sharp, F.R., Richtand, N.M. Brain Res. Bull. (2006) [Pubmed]
  10. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Van Tol, H.H., Bunzow, J.R., Guan, H.C., Sunahara, R.K., Seeman, P., Niznik, H.B., Civelli, O. Nature (1991) [Pubmed]
  11. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Bianco, A.C., Salvatore, D., Gereben, B., Berry, M.J., Larsen, P.R. Endocr. Rev. (2002) [Pubmed]
  12. Type 3 lodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme. Salvatore, D., Low, S.C., Berry, M., Maia, A.L., Harney, J.W., Croteau, W., St Germain, D.L., Larsen, P.R. J. Clin. Invest. (1995) [Pubmed]
  13. G protein activation by human dopamine D3 receptors in high-expressing Chinese hamster ovary cells: A guanosine-5'-O-(3-[35S]thio)- triphosphate binding and antibody study. Newman-Tancredi, A., Cussac, D., Audinot, V., Pasteau, V., Gavaudan, S., Millan, M.J. Mol. Pharmacol. (1999) [Pubmed]
  14. Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins. Xu, Y., Chen, S.Y., Ross, K.N., Balk, S.P. Cancer Res. (2006) [Pubmed]
  15. Staphylococcus saprophyticus hemagglutinin binds fibronectin. Gatermann, S., Meyer, H.G. Infect. Immun. (1994) [Pubmed]
  16. Localization of the type 3 iodothyronine deiodinase (DIO3) gene to human chromosome 14q32 and mouse chromosome 12F1. Hernandez, A., Park, J.P., Lyon, G.J., Mohandas, T.K., St Germain, D.L. Genomics (1998) [Pubmed]
  17. Substitution of cysteine for selenocysteine in the catalytic center of type III iodothyronine deiodinase reduces catalytic efficiency and alters substrate preference. Kuiper, G.G., Klootwijk, W., Visser, T.J. Endocrinology (2003) [Pubmed]
  18. Structure and function of the type 3 deiodinase gene. Hernandez, A. Thyroid (2005) [Pubmed]
  19. Complex organization and structure of sense and antisense transcripts expressed from the DIO3 gene imprinted locus. Hernandez, A., Martinez, M.E., Croteau, W., St Germain, D.L. Genomics (2004) [Pubmed]
  20. Dopamine D2 receptor-mediated G-protein activation in rat striatum: functional autoradiography and influence of unilateral 6-hydroxydopamine lesions of the substantia nigra. Newman-Tancredi, A., Cussac, D., Brocco, M., Rivet, J.M., Chaput, C., Touzard, M., Pasteau, V., Millan, M.J. Brain Res. (2001) [Pubmed]
  21. S 16924 ((R)-2-[1-[2-(2,3-dihydro-benzo[1,4] dioxin-5-Yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), a novel, potential antipsychotic with marked serotonin (5-HT)1A agonist properties: I. Receptorial and neurochemical profile in comparison with clozapine and haloperidol. Millan, M.J., Gobert, A., Newman-Tancredi, A., Audinot, V., Lejeune, F., Rivet, J.M., Cussac, D., Nicolas, J.P., Muller, O., Lavielle, G. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  22. S 18126 ([2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl methyl]indan-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-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2, 3b]pyridine) and raclopride. Millan, M.J., Newman-Tancredi, A., Brocco, M., Gobert, A., Lejeune, F., Audinot, V., Rivet, J.M., Schreiber, R., Dekeyne, A., Spedding, M., Nicolas, J.P., Peglion, J.L. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
  23. Transforming growth factor-beta promotes inactivation of extracellular thyroid hormones via transcriptional stimulation of type 3 iodothyronine deiodinase. Huang, S.A., Mulcahey, M.A., Crescenzi, A., Chung, M., Kim, B.W., Barnes, C., Kuijt, W., Turano, H., Harney, J., Larsen, P.R. Mol. Endocrinol. (2005) [Pubmed]
  24. IL-2-dependent induction of G1 cyclins in primary T cells is not blocked by rapamycin or cyclosporin A. Turner, J.M. Int. Immunol. (1993) [Pubmed]
  25. Actions of roxindole at recombinant human dopamine D2, D3 and D4 and serotonin 5-HT1A, 5-HT1B and 5-HT1D receptors. Newman-Tancredi, A., Cussac, D., Audinot, V., Millan, M.J. Naunyn Schmiedebergs Arch. Pharmacol. (1999) [Pubmed]
  26. Somatosensory cortical plasticity in carpal tunnel syndrome--a cross-sectional fMRI evaluation. Napadow, V., Kettner, N., Ryan, A., Kwong, K.K., Audette, J., Hui, K.K. Neuroimage (2006) [Pubmed]
  27. D2-like dopamine receptors are not detectable on human peripheral blood lymphocytes. Vile, J.M., Strange, P.G. Biol. Psychiatry (1996) [Pubmed]
  28. Ontogeny of iodothyronine deiodinases in human liver. Richard, K., Hume, R., Kaptein, E., Sanders, J.P., van Toor, H., De Herder, W.W., den Hollander, J.C., Krenning, E.P., Visser, T.J. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
  29. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. Peeters, R.P., Wouters, P.J., Kaptein, E., van Toor, H., Visser, T.J., Van den Berghe, G. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
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