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      The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications

      1 , 1 , 1 , 2 , 1

      Annual Review of Physiology

      Annual Reviews

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          Abstract

          <p class="first" id="P1">Active iodide (I <sup>−</sup>) transport in both the thyroid and some extrathyroidal tissues is mediated by the N a <sup>+</sup>/I <sup>−</sup> symporter (NIS). In the thyroid, NIS-mediated I <sup>−</sup> uptake plays a pivotal role in thyroid hormone (TH) biosynthesis. THs are key during embryonic and postembryonic development and critical for cell metabolism at all stages of life. The molecular characterization of NIS in 1996 and the use of radioactive I <sup>−</sup> isotopes have led to significan advances in the diagnosis and treatment of thyroid cancer and provide the molecular basis for studies aimed at extending the use of radioiodide treatment in extrathyroidal malignancies. This review focuses on the most recent finding on I <sup>−</sup> homeostasis and I <sup>−</sup> transport deficiency-causin NIS mutations, as well as current knowledge of the structure/function properties of NIS and NIS regulatory mechanisms. We also discuss employing NIS as a reporter gene using viral vectors and stem cells in imaging, diagnostic, and therapeutic procedures. </p>

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          Most cited references 133

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          Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters.

          Na+/Cl--dependent transporters terminate synaptic transmission by using electrochemical gradients to drive the uptake of neurotransmitters, including the biogenic amines, from the synapse to the cytoplasm of neurons and glia. These transporters are the targets of therapeutic and illicit compounds, and their dysfunction has been implicated in multiple diseases of the nervous system. Here we present the crystal structure of a bacterial homologue of these transporters from Aquifex aeolicus, in complex with its substrate, leucine, and two sodium ions. The protein core consists of the first ten of twelve transmembrane segments, with segments 1-5 related to 6-10 by a pseudo-two-fold axis in the membrane plane. Leucine and the sodium ions are bound within the protein core, halfway across the membrane bilayer, in an occluded site devoid of water. The leucine and ion binding sites are defined by partially unwound transmembrane helices, with main-chain atoms and helix dipoles having key roles in substrate and ion binding. The structure reveals the architecture of this important class of transporter, illuminates the determinants of substrate binding and ion selectivity, and defines the external and internal gates.
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            Cloning and characterization of the thyroid iodide transporter.

             J-G Dai,  N Carrasco,  O Levy (1996)
            Iodide (I-) is an essential constituent of the thyroid hormones T3 and T4, and is accumulated by the thyroid. The transport of iodide, the first step in thyroid hormogenesis, is catalysed by the Na+/I- symporter, an intrinsic membrane protein that is crucial for the evaluation, diagnosis and treatment of thyroid disorders. Although several other important thyroid proteins involved in hormogenesis have been characterized, the Na+/I- symporter has not. Here we report the isolation of a complementary DNA clone that encodes this symporter, as a result of functional screening of a cDNA library from a rat thyroid-derived cell line (FRTL-5) in Xenopus laevis oocytes. Oocyte microinjection of an RNA transcript made in vitro from this cDNA clone elicited a more than 700-fold increase in perchlorate-sensitive Na+/I- symport activity over background. To our knowledge, this is the first iodide-transporting molecule to have its cDNA cloned, providing a missing link in the thyroid hormone biosynthetic pathway.
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              Remission of disseminated cancer after systemic oncolytic virotherapy.

              MV-NIS is an engineered measles virus that is selectively destructive to myeloma plasma cells and can be monitored by noninvasive radioiodine imaging of NIS gene expression. Two measles-seronegative patients with relapsing drug-refractory myeloma and multiple glucose-avid plasmacytomas were treated by intravenous infusion of 10(11) TCID50 (50% tissue culture infectious dose) infectious units of MV-NIS. Both patients responded to therapy with M protein reduction and resolution of bone marrow plasmacytosis. Further, one patient experienced durable complete remission at all disease sites. Tumor targeting was clearly documented by NIS-mediated radioiodine uptake in virus-infected plasmacytomas. Toxicities resolved within the first week after therapy. Oncolytic viruses offer a promising new modality for the targeted infection and destruction of disseminated cancer.
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                Author and article information

                Journal
                Annual Review of Physiology
                Annu. Rev. Physiol.
                Annual Reviews
                0066-4278
                1545-1585
                February 10 2017
                February 10 2017
                : 79
                : 1
                : 261-289
                Affiliations
                [1 ]Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut 06510; email:
                [2 ]Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
                Article
                10.1146/annurev-physiol-022516-034125
                5739519
                28192058
                © 2017

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