The Na+/I- symporter (NIS) is the key plasma membrane protein that mediates active I- transport in the thyroid, the first step in the biosynthesis of the thyroid hormones. NIS is also the molecule at the center of the most successful targeted internal radiation cancer treatment ever devised: 131I- therapy of thyroid cancer administered post-thyroidectomy. The initial launching of this project resulted in the cloning of the cDNA that encodes NIS, a major breakthrough in thyroid research that had been sought for decades. Since then, this project has (in subsequent funding cycles) yielded many other major advances, including a wealth of structure/function and mechanistic information on NIS, and highly revealing findings about its regulation, biogenesis, posttranslational modifications, and expression in extrathyroidal tissues, including primary and metastatic breast cancer. We have also discovered that NIS transports different anion substrates with different stoichiometries, a significant mechanistic property that has not been described for any other transporters to date. The current proposal focuses on a newly discovered regulatory crosstalk interaction that takes place in thyroid cells between NIS and a K+ channel, KCNQ1-KCNE2, thereby beginning a new chapter in our study of NIS regulation. This NIS/KCNQ1-KCNE2 regulatory interaction was the first transporter/channel interaction ever to be identified. KCNQ1 is a voltage-gated potassium (Kv) channel ?ubunit essential for the repolarization of the cardiac ventricles, and KCNE2, the channel ?ubunit, is the product of one of five members of a gene family that can regulate KCNQ1. KCNQ1 and KCNE2 each perform essential roles in human ventricular myocytes, but we discovered that they also form a heteromeric channel together in the plasma membrane of thyrocytes, as well as in other epithelial tissues. Surprisingly, knockout mice devoid of either KCNQ1 or KCNE2, in addition to the expected cardiac manifestations, also develop hypothyroidism, because KCNQ1-KCNE2 plays a crucial role in thyroid function by increasing NIS activity. We have also shown that NIS, in turn, stimulates the activity of KCNQ1-KCNE2. The goal of this proposal is to elucidate the underlying mechanisms of the bi-directional regulatory interaction between NIS and KCNQ1-KCNE2 and to investigate the role of the other KCNE subunits in NIS regulation and thyroid physiology. We will pursue the following Aims: 1.To ascertain when and where in the biosynthetic pathway the NIS/Q1-E2 interaction occurs. 2.To test the hypothesis that the increase in NIS activity caused by Q1-E2 results from a local change in the membrane potential (? brought about by the activity of Q1-E2. 3. To determine which domains of NIS and Q1 participate in the interaction between these two proteins. 4. To elucidate the roles of KCNE ancillary subunits 1, 3, 4, and 5 in the regulation of NIS activity and thyroid function by Q1 and, conversely, of Q1 activity by NIS. This research is likely to spur interest in the analysis of other such transporter-channel interactions, which may also prove to be physiologically and clinically significant.

Public Health Relevance

The purpose of this project is to carry out a detailed study of a novel mode of regulation of a key protein, the sodium/iodide symporter (NIS), a molecule present most notably in the thyroid gland, where it is responsible for the crucial first step in th production of the thyroid hormones. One of our research groups was the first to clone and characterize NIS, and in collaboration with the other one has shown that, unexpectedly, NIS is regulated by a membrane protein of a different sort-a potassium channel-which is therefore critical for thyroid function. In this project, our two groups will combine their different types o expertise to obtain mechanistic information on how this regulation occurs, which will likely enhance considerably our understanding of this crucial protein and of other transporters.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Malozowski, Saul N
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Yale University
Schools of Medicine
New Haven
United States
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Ravera, Silvia; Carrasco, Nancy; Gelernter, Joel et al. (2018) Phenomic Impact of Genetically-Determined Euthyroid Function and Molecular Differences between Thyroid Disorders. J Clin Med 7:
Ferrandino, Giuseppe; Kaspari, Rachel R; Spadaro, Olga et al. (2017) Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms. Proc Natl Acad Sci U S A 114:E9172-E9180
Ravera, Silvia; Reyna-Neyra, Andrea; Ferrandino, Giuseppe et al. (2017) The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications. Annu Rev Physiol 79:261-289
Ferrandino, Giuseppe; Kaspari, Rachel R; Reyna-Neyra, Andrea et al. (2017) An extremely high dietary iodide supply forestalls severe hypothyroidism in Na+/I- symporter (NIS) knockout mice. Sci Rep 7:5329
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Abbott, Geoffrey W (2016) Channel-transporter complexes: an emerging theme in cell signaling. Biochem J 473:3759-3763

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