Taroh Iiri

The University of Tokyo, Tōkyō, Japan

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Publications (59)432.11 Total impact

  • A. Oishi · Noriko Makita · K. Manaka · K. Mitani · H. Tomita · T. Iiri ·

    Diabetology International 07/2015; DOI:10.1007/s13340-015-0220-4
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    Taroh Iiri · Noriko Makita ·

    Folia Pharmacologica Japonica 01/2015; 145(1):10-13. DOI:10.1254/fpj.145.10
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    Nihon Naika Gakkai Zasshi 05/2014; 103(5):1180-2. DOI:10.2169/naika.103.1180
  • Katsunori Manaka · Noriko Makita · Taroh Iiri ·
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    ABSTRACT: An early thirties man diagnosed with Erdheim-Chester disease (ECD) was simultaneously disclosed to have hypogonadotropic hypogonadism, central adrenal insufficiency, and GH deficiency in addition to central diabetes insipidus (CDI). Pituitary magnetic resonance imaging (MRI) showed swelling in the stalk, enlargement of the anterior lobe with delayed enhancement, and loss of high intensity of the posterior lobe on T1-weighted images, suggesting of pituitary involvement of ECD. Three months after starting treatment with interferon α and zoledronic acid, polyuria and polydipsia were ameliorated without DDAVP, accompanied with improvement of MRI. Simultaneously technetium-99m bone scintigraphy showed improvement, accompanied with a relief of bone pain and high fever. In contrast, he developed secondary hypothyroidism with slight enlargement of anterior pituitary gland without relapse of CDI, suggesting of different responses to treatment with interferon α between anterior pituitary lobe and posterior one. So far he continues to be replaced with deficient hormone replacement therapy. As for bone pain, it remains to be controlled with the decreased levels of bone resorption marker with decreased abnormal uptake in bone scintigraphy although zoledronic acid was discontinued for osteonecrosis of the jaw. For four years, he has not showed new involvement at other organs besides bones and the pituitary. While CDI is known to be very common in ECD, improvement of CDI has been reported in a few cases. Other endocrine manifestations, especially with detailed endocrine status, have been also reported in limited cases. Thus we report this case and review the literature.
    Endocrine Journal 12/2013; 61(2). DOI:10.1507/endocrj.EJ13-0419 · 2.00 Impact Factor
  • Noriko Makita · Taroh Iiri ·
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    ABSTRACT: The classical model of G protein-coupled receptor (GPCR) activation is the two-state model, in which the GPCR exists in equilibrium between an active and inactive state. Based on this model, GPCR ligands have been classified as agonists, inverse agonists, or antagonists depending on their actions in shifting this equilibrium. Recently, however, accumulating evidence has indicated that GPCRs may exist in multiple active and inactive conformational states. In this situation, each ligand recognizes and stabilizes a specific conformation of the GPCR, leading to a set of specific biological effects. Based on this new model, a unique agonist or a combination of the usual agonist and an allosteric modulator may enable activation of a specific signaling pathway via a GPCR that activates multiple signals (biased agonism, functional selectivity). The calcium-sensing receptor autoantibody that we have identified in the serum of a patient with acquired hypocalciuric hypercalcemia (AHH) is the first example of a biased allosteric modulator of a GPCR working in a pathophysiological context. Our findings may indicate the presence of physiological allosteric modulators and provide new directions for the future drug development.
    Endocrine Journal 11/2013; 61(4). DOI:10.1507/endocrj.EJ13-0453 · 2.00 Impact Factor

  • Journal of cardiothoracic and vascular anesthesia 08/2013; 28(1). DOI:10.1053/j.jvca.2012.07.010 · 1.46 Impact Factor
  • Noriko Makita · Taroh Iiri ·
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    ABSTRACT: Background: Thyroid dysfunction is a well-known adverse effect of sunitinib, a drug that targets multiple receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR). As several kinds of tyrosine kinase inhibitors (TKIs) are now available, this has been postulated to be a side effect of the TKIs that target the VEGFR (VEGF-TKIs). However, sunitinib, one of the first-generation TKIs, likely causes thyroid dysfunction more frequently than other TKI classes, leading not only to hypothyroidism, but also to thyrotoxicosis. Summary: Based on the reports published to date, including our own studies, we have hypothesized that sunitinib may exert these effects, because it targets a broad spectrum of tyrosine kinases. This not only includes VEGFR2, but also VEGFR1 and the platelet-derived growth factor receptor (PDGFR). This, in turn, may suggest that not only VEGFR2 but also the PDGFR and/or the VEGFR1 play an important role during angiogenesis in the thyroid. Conclusions: Our current hypothesis may explain the mechanisms that underlie TKI-induced thyroid disorders. By learning how various kinds of TKIs affect thyroid function, we may elucidate how the angiogenesis in thyroid is regulated both physiologically and pathologically.
    Thyroid: official journal of the American Thyroid Association 02/2013; 23(2):151-9. DOI:10.1089/thy.2012.0456 · 4.49 Impact Factor
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    ABSTRACT: Rationale: The clinical problem of loss of β-adrenergic receptor (β-AR) response, both in the pathogenesis of heart failure and during therapeutic application of β-agonists, is attributable, at least in part, to desensitization, internalization, and downregulation of the receptors. In the regulation of β-AR signaling, G protein-coupled receptor kinase 2 (GRK2) primarily phosphorylates agonist-occupied β-ARs, and this modification promotes desensitization, internalization, and downregulation of β-ARs. It has been demonstrated that GRK2 is inhibited by its S-nitrosylation. However, compounds that induce S-nitrosylation, such as S-nitrosoglutathione, simultaneously generate NO, which has been demonstrated to operate for cardiovascular protection. Objective: We examine whether S-nitrosylation without NO generation inhibits desensitization of β(2)-AR by GRK2. We thus aim to synthesize compounds that specifically induce S-nitrosylation. Methods and results: We have developed water-soluble N-nitrosamines that have S-nitrosylating activity but lack NO-generating activity. These compounds, at least partly, rescue β-AR from desensitization in HEK 293 cells expressing FLAG-tagged human β(2)-AR and in rat cardiac myocytes. They inhibit isoproterenol-dependent phosphorylation and internalization of β(2)-AR. Indeed, they nitrosylate GRK2 in vitro and in cells, and their S-nitrosylation of GRK2 likely underlies their inhibition of β(2)-AR desensitization. Conclusions: Compounds that induce S-nitrosylation without NO release inhibit GRK2 and attenuate β(2)-AR desensitization. Developing water-soluble drugs that specifically induce S-nitrosylation may be a promising therapeutic strategy for heart failure.
    Circulation Research 12/2012; 112(2). DOI:10.1161/CIRCRESAHA.112.277665 · 11.02 Impact Factor
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    Atsuro Oishi · Noriko Makita · Junichiro Sato · Taroh Iiri ·
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    ABSTRACT: RhoA plays a pivotal role in regulating cell shape and movement. Protein kinase A (PKA) inhibits RhoA signaling and thereby induces a characteristic morphological change, cell rounding. This has been considered to result from cAMP-induced phosphorylation of RhoA at Ser-188, which induces a stable RhoA-GTP-RhoGDIα complex and sequesters RhoA to the cytosol. However, few groups have shown RhoA phosphorylation in intact cells. Here we show that phosphorylation of RhoGDIα but not RhoA plays an essential role in the PKA-induced inhibition of RhoA signaling and in the morphological changes using cardiac fibroblasts. The knockdown of RhoGDIα by siRNA blocks cAMP-induced cell rounding, which is recovered by RhoGDIα-WT expression but not when a RhoGDIα-S174A mutant is expressed. PKA phosphorylates RhoGDIα at Ser-174 and the phosphorylation of RhoGDIα is likely to induce the formation of a active RhoA-RhoGDIα complex. Our present results thus reveal a principal molecular mechanism underlying Gs/cAMP-induced cross-talk with Gq/G13/RhoA signaling.
    Journal of Biological Chemistry 09/2012; 287(46). DOI:10.1074/jbc.M112.401547 · 4.57 Impact Factor
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    ABSTRACT: Inactivating mutations of the V2 vasopressin receptor (V2R) cause cross-linked congenital nephrogenic diabetes insipidus (NDI), resulting in renal resistance to the antidiuretic hormone AVP. In two families showing partial NDI, characterized by an apparently normal response to diagnostic tests and an increase in the basal ADH levels suggesting AVP resistance, we have identified two V2R mutations, Ser-333del and Y128S. Both mutant V2Rs, when expressed in COS-7 cells, show partial defects in vasopressin-stimulated cAMP accumulation and intracellular localization. The inhibition of internalization does not rescue their localization. In contrast, the non-peptide V2R antagonists OPC41061 and OPC31260 partially rescue the membrane localization and basal function of these V2R mutants, whereas they inhibit the basal activity of the wild-type V2R. These results indicate that a partial loss of function of Ser-333del and Y128S mutant V2Rs results from defective membrane trafficking. These findings further indicate that V2R antagonists can act as protean agonists, serving as pharmacological chaperones for inactivating V2R mutants and also as inverse agonists of wild-type receptors. We speculate that this protean agonism could underlie the possible dual beneficial effects of the V2R antagonist: improvement of hyponatremia with heart failure or polycystic kidney disease and potential rescue of NDI.
    Journal of Biological Chemistry 12/2011; 287(3):2099-106. DOI:10.1074/jbc.M111.268797 · 4.57 Impact Factor

  • Thyroid: official journal of the American Thyroid Association 08/2011; 21(10):1157-8. DOI:10.1089/thy.2010.0352 · 4.49 Impact Factor
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    ABSTRACT: A 70-year old man with a 14 year history of Sjögren syndrome, interstitial pneumonia, and autoimmune hepatitis (AIH) was admitted to our hospital due to hyponatremia with a one month history of fatigue, thirst, and nausea. Laboratory tests on admission revealed that this patient had a central adrenal insufficiency. Pituitary magnetic resonance imaging (MRI) further showed swelling of the stalk and posterior lobe of his pituitary, suggesting infundibulo-hypophysitis. Based on his past history of autoimmune disease, his serum IgG4 levels were measured and found to be remarkably high (924 mg/ dL). Previous biopsy specimens from his liver, lung, and parotid gland were immunostained for IgG4, which revealed a marked infiltration of IgG4-positive plasma cells. As a result of our tests, we made a diagnosis of IgG4-related systemic disease. Interestingly, a subsequent MRI scan at three weeks after the patient commenced glucocorticoid replacement therapy for adrenal insufficiency showed that the swelling of his pituitary stalk was reduced. This finding suggested that IgG4-related hypophysitis may improve either as a result of a supplemental dose of glucocorticoid or possibly spontaneously. Although six cases of IgG4-related hypophysitis have been reported in the scientific literature published in English, our current case is the first in which IgG4-related hypophysitis likely occurred as a result of a long-term history of IgG4-related systemic disease. We report this case herein and review the relevant literature.
    Endocrine Journal 04/2010; 57(6):485-92. DOI:10.1507/endocrj.K09E-356 · 2.00 Impact Factor
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    ABSTRACT: Sunitinib is a small molecule that inhibits receptor tyrosine kinases, including the vascular endothelial growth factor receptors, and exhibits antiangiogenic and antitumor activity. This molecule has also been reported to cause hypothyroidism at a high frequency, but the mechanism of this is unknown. A 60-year-old woman was administered sunitinib for the treatment of metastatic renal cell carcinoma. One week later, she displayed overt hypothyroidism with an atrophic thyroid and a marked reduction in vascularity as determined by ultrasonography, despite high levels of thyrotropin. In contrast, during the off-periods in the sunitinib treatment cycles, the volume of her thyroid recovered with an increase in vascularity despite a low level of thyrotropin. These results suggest that thyroid function and volume may depend on the vascularity, which is negatively regulated by sunitinib. Our case study provides compelling evidence that sunitinib induces hypothyroidism by reducing blood flow via capillary regression and constriction.
    Thyroid: official journal of the American Thyroid Association 03/2010; 20(3):323-6. DOI:10.1089/thy.2009.0414 · 4.49 Impact Factor
  • Taroh Iiri · Noriko Makita ·

    Folia Pharmacologica Japonica 11/2009; 134(5):244-7. DOI:10.1254/fpj.134.244
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    ABSTRACT: It has been suggested previously ( AbdAlla, S., Lother, H., and Quitterer, U. (2000) Nature 407, 94-98 ) that the angiotensin II type 1 receptor (AT1R) and the bradykinin B2 receptor (B2R) form constitutive heterodimers. Furthermore they demonstrate that AT1R signaling significantly increases in the presence of the B2R. These findings suggest that heterodimerization and potentiation of AT1R signaling is a universal phenomenon that occurs as a natural consequence of simultaneous expression of the two receptors. Hence this potential interaction is of great pharmacological and biological interest that adds an additional layer of complexity to the understanding of the cross-talk between the renin-angiotensin and kallikrein-kinin systems. Given the remarkable significance of this finding, scientists from four independent research groups have set out to reproduce and further examine the potential AT1R/B2R interaction. We have investigated functional potentiation by the B2R of AT1R signaling in three different cell lines using multiple assays including phosphoinositide hydrolysis, ERK activation, beta-arrestin recruitment, and receptor selection and amplification technology, and we have examined dimerization using bioluminescence resonance energy transfer and regulated secretion/aggregation technology. However, although both the AT1Rs and B2Rs were functional in our systems and the systems were fine tuned to detect small changes in receptor function, we failed to detect any functional modulation by or physical interaction between the two receptor proteins. In contrast to the previous observations, our data collectively suggest that AT1R/B2R heterodimerization does not occur as a natural consequence of their simultaneous expression in the same cell nor does the B2R influence the AT1R signaling.
    Journal of Biological Chemistry 12/2008; 284(3):1831-9. DOI:10.1074/jbc.M804607200 · 4.57 Impact Factor
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    ABSTRACT: Pseudohypoparathyroidism type Ia (PHP-Ia) results from the loss of one allele of G(salpha), causing resistance to parathyroid hormone and other hormones that transduce signals via G(s). Most G(salpha)mutations cause the complete loss of protein expression, but some cause loss of function only, and these have provided valuable insights into the normal function of G proteins. Here we have analyzed a mutant G(salpha) (alphas-AVDT) harboring AVDT amino acid repeats within its GDP/GTP binding site, which was identified in unique patients with PHP-Ia accompanied by neonatal diarrhea. Biochemical and intact cell analyses showed that alphas-AVDT is unstable but constitutively active as a result of rapid GDP release and reduced GTP hydrolysis. This instability underlies the PHP-Ia phenotype. alphas-AVDT is predominantly localized in the cytosol, but in rat and mouse small intestine epithelial cells (IEC-6 and DIF-12 cells) alphas-AVDT was found to be localized predominantly in the membrane where adenylyl cyclase is present and constitutive increases in cAMP accumulation occur in parallel. The likely cause of this membrane localization is the inhibition of an activation-dependent decrease in alphas palmitoylation. Upon the overexpression of acyl-protein thioesterase 1, however, alphas-AVDT translocates from the membrane to the cytosol, and the constitutive accumulation of cAMP becomes attenuated. These results suggest that PHP-Ia results from the instability of alphas-AVDT and that the accompanying neonatal diarrhea may result from its enhanced constitutive activity in the intestine. Hence, palmitoylation may control the activity and localization of G(salpha) in a cell-specific manner.
    Proceedings of the National Academy of Sciences 11/2007; 104(44):17424-9. DOI:10.1073/pnas.0708561104 · 9.67 Impact Factor
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    ABSTRACT: The seven-spanning calcium-sensing receptor (CaSR) activates multiple G proteins including Gq and Gi, and thereby activates a variety of second messengers and inhibits parathyroid hormone (PTH) secretion. However, the exact signaling mechanisms underlying the functional activity of CaSR are not yet fully understood. The heterozygous inactivation of CaSR or its inhibition by antibody blocking results in either familial hypocalciuric hypercalcemia or acquired hypocalciuric hypercalcemia (AHH), respectively. Here, we report the identification of a unique CaSR autoantibody in an AHH patient. Paradoxically, we find that this autoantibody potentiates the Ca(2+)/Gq-dependent accumulation of inositol phosphates by slightly shifting the dose dependence curve of the Ca(2+) mediated activation of phosphatidylinositol turnover to the left, whereas it inhibits the Ca(2+)/Gi-dependent phosphorylation of ERK1/2 in HEK293 cells stably expressing human CaSR. Treatment of these same cells with a calcimimetic, NPS-R-568, augments the CaSR response to Ca(2+), increasing phosphatidylinositol turnover and ERK1/2 phosphorylation, and overcoming the autoantibody effects. Our observations thus indicate that a calcium-stimulated CaSR primed by a specific autoantibody adopts a unique conformation that activates Gq but not Gi. Our findings also suggest that CaSR signaling may act via both Gq and Gi to inhibit PTH secretion. This is the first report of a disease-related autoantibody that functions as an allosteric modulator and maintains G protein-coupled receptors (GPCRs) in a unique active conformation with its agonist. We thus speculate that physiological modulators may exist that enable an agonist to specifically activate only one signaling pathway via a GPCR that activates multiple signaling pathways.
    Proceedings of the National Academy of Sciences 04/2007; 104(13):5443-8. DOI:10.1073/pnas.0701290104 · 9.67 Impact Factor
  • Noriko Makita · Toshiro Fujita · Taroh Iiri ·

    AfCS-Nature Molecule Pages 11/2006; DOI:10.1038/mp.a000275.01
  • Noriko Makita · Taroh Iiri ·

    Nippon rinsho. Japanese journal of clinical medicine 08/2006; 64 Suppl 5:192-6.
  • Katsunori Manaka · Noriko Makita · Taroh Iiri ·

    Nippon rinsho. Japanese journal of clinical medicine 08/2006; 64 Suppl 5:407-10.

Publication Stats

2k Citations
432.11 Total Impact Points


  • 2005-2014
    • The University of Tokyo
      • Department of Nephrology and Endocrinology
      Tōkyō, Japan
  • 1996-2000
    • University of California, San Francisco
      • Department of Cellular and Molecular Pharmacology
      San Francisco, CA, United States
  • 1999
    • Cardiovascular Research Foundation
      New York, New York, United States
  • 1997
    • Thomas Jefferson University
      Philadelphia, Pennsylvania, United States
  • 1995
    • CSU Mentor
      Long Beach, California, United States
  • 1989-1995
    • Tokyo Institute of Technology
      • Department of Life Science
      Tokyo, Tokyo-to, Japan