The Iodide Transport Defect-Causing Y348D Mutation in the Na/I Symporter Renders the Protein Intrinsically Inactive and Impairs Its Targeting to the Plasma Membrane.

The sodium/iodide (Na/I) symporter (NIS) mediates active transport of I into the thyroid gland. Mutations in the gene, which encodes NIS, cause I transport defects (ITDs)-which, if left untreated, lead to congenital hypothyroidism and consequent cognitive and developmental deficiencies. The ITD-causing NIS mutation Y348D, located in transmembrane segment (TMS) 9, was reported in three Sudanese patients.

The paradoxical lean phenotype of hypothyroid mice is marked by increased adaptive thermogenesis in the skeletal muscle.

Obesity is a major health problem worldwide, given its growing incidence and its association with a variety of comorbidities. Weight gain results from an increase in energy intake without a concomitant increase in energy expenditure. To combat the obesity epidemic, many studies have focused on the pathways underlying satiety and hunger signaling, while other studies have concentrated on the mechanisms involved in energy expenditure, most notably adaptive thermogenesis.

Author Correction: Allosteric regulation of mammalian Na/I symporter activity by perchlorate.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Allosteric regulation of mammalian Na/I symporter activity by perchlorate.

The Na/I symporter (NIS), the plasma membrane protein that actively transports I (stoichiometry 2Na:1I) in thyroid physiology and radioiodide-based thyroid cancer treatment, also transports the environmental pollutant perchlorate (stoichiometry 1Na:1ClO), which competes with I for transport. Until now, the mechanism by which NIS transports different anion substrates with different stoichiometries has remained unelucidated. We carried out transport measurements and analyzed these using a statistical thermodynamics-based equation and electrophysiological experiments to show that the different stoichiometry of ClO transport is due to ClO binding to a high-affinity non-transport allosteric site that prevents Na from binding to one of its two sites.

Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms.

Hypothyroidism, a metabolic disease characterized by low thyroid hormone (TH) and high thyroid-stimulating hormone (TSH) levels in the serum, is strongly associated with nonalcoholic fatty liver disease (NAFLD). Hypothyroidism-induced NAFLD has generally been attributed to reduced TH signaling in the liver with a consequent decrease in lipid utilization. Here, we found that mildly hypothyroid mice develop NAFLD without down-regulation of hepatic TH signaling or decreased hepatic lipid utilization.

An extremely high dietary iodide supply forestalls severe hypothyroidism in Na/I symporter (NIS) knockout mice.

The sodium/iodide symporter (NIS) mediates active iodide (I) accumulation in the thyroid, the first step in thyroid hormone (TH) biosynthesis. Mutations in the SLC5A5 gene encoding NIS that result in a non-functional protein lead to congenital hypothyroidism due to I transport defect (ITD). ITD is a rare autosomal disorder that, if not treated promptly in infancy, can cause mental retardation, as the TH decrease results in improper development of the nervous system.

mTORC1 Balances Cellular Amino Acid Supply with Demand for Protein Synthesis through Post-transcriptional Control of ATF4.

The mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that is commonly deregulated in human diseases. Here we find that mTORC1 controls a transcriptional program encoding amino acid transporters and metabolic enzymes through a mechanism also used to regulate protein synthesis. Bioinformatic analysis of mTORC1-responsive mRNAs identified a promoter element recognized by activating transcription factor 4 (ATF4), a key effector of the integrated stress response.

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

Active iodide (I) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na/I symporter (NIS). In the thyroid, NIS-mediated I 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.

Regression of experimental NIS-expressing breast cancer brain metastases in response to radioiodide/gemcitabine dual therapy.

Treating breast cancer brain metastases (BCBMs) is challenging. Na+/I- symporter (NIS) expression in BCBMs would permit their selective targeting with radioiodide (131I-). We show impressive enhancement of tumor response by combining131I- with gemcitabine (GEM), a cytotoxic radiosensitizer.

Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells.

The aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs), cancers occurring increasingly in children to young adults, is poorly understood. We present a transplantable tumour line, maintained in immune-compromised mice, and validate it as a bona fide model of hFL-HCCs by multiple methods. RNA-seq analysis confirms the presence of a fusion transcript (DNAJB1-PRKACA) characteristic of hFL-HCC tumours.

Sodium/Iodide Symporter Mutant V270E Causes Stunted Growth but No Cognitive Deficiency.

Context: Iodide (I(-)), an essential constituent of the thyroid hormones, is actively accumulated in the thyroid by the Na(+)/I(-) symporter (NIS), a key plasma membrane protein encoded by the slc5a5 gene. Mutations in slc5a5 cause I(-) transport defects (ITDs), autosomal-recessive disorders in which I(-) accumulation is totally or partially impaired, leading to congenital hypothyroidism. The characterization of NIS mutants has yielded significant insights into the molecular mechanism of NIS.

Dietary iodide controls its own absorption through post-transcriptional regulation of the intestinal Na+/I- symporter.

Dietary I(-) absorption in the gastrointestinal tract is the first step in I(-) metabolism. Given that I(-) is an essential constituent of the thyroid hormones, its concentrating mechanism is of significant physiological importance. We recently described the expression of the Na(+)/I(-) symporter (NIS) on the apical surface of the intestinal epithelium as a central component of the I(-) absorption system and reported reduced intestinal NIS expression in response to an I(-)-rich diet in vivo.

The KCNQ1-KCNE2 K⁺ channel is required for adequate thyroid I⁻ uptake.

The KCNQ1 α subunit and the KCNE2 β subunit form a potassium channel in thyroid epithelial cells. Genetic disruption of KCNQ1-KCNE2 causes hypothyroidism in mice, resulting in cardiac hypertrophy, dwarfism, alopecia, and prenatal mortality. Here, we investigated the mechanistic requirement for KCNQ1-KCNE2 in thyroid hormone biosynthesis, utilizing whole-animal dynamic positron emission tomography.

Mechanism of anion selectivity and stoichiometry of the Na+/I- symporter (NIS).

I(-) uptake in the thyroid, the first step in thyroid hormone biosynthesis, is mediated by the Na(+)/I(-) symporter (NIS) with an electrogenic 2Na(+):1I(-) stoichiometry. We have obtained mechanistic information on NIS by characterizing the congenital I(-) transport defect-causing NIS mutant G93R. This mutant is targeted to the plasma membrane but is inactive.

Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis.

Thyroid dysfunction is a global health concern, causing defects including neurodevelopmental disorders, dwarfism and cardiac arrhythmia. Here, we show that the potassium channel subunits KCNQ1 and KCNE2 form a thyroid-stimulating hormone-stimulated, constitutively active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis. Targeted disruption of Kcne2 in mice impaired thyroid iodide accumulation up to eightfold, impaired maternal milk ejection, halved milk tetraiodothyronine (T4) content and halved litter size.

The Na+/I- symporter mediates active iodide uptake in the intestine.

Absorption of dietary iodide, presumably in the small intestine, is the first step in iodide (I(-)) utilization. From the bloodstream, I(-) is actively taken up via the Na(+)/I(-) symporter (NIS) in the thyroid for thyroid hormone biosynthesis and in such other tissues as lactating breast, which supplies I(-) to the newborn in the milk. The molecular basis for intestinal I(-) absorption is unknown.

The Na+/I symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate.

The Na(+)/I(-) symporter (NIS) is a key plasma membrane protein that mediates active I(-) uptake in the thyroid, lactating breast, and other tissues with an electrogenic stoichiometry of 2 Na(+) per I(-). In the thyroid, NIS-mediated I(-) uptake is the first step in the biosynthesis of the iodine-containing thyroid hormones, which are essential early in life for proper CNS development. In the lactating breast, NIS mediates the translocation of I(-) to the milk, thus supplying this essential anion to the nursing newborn.

Regional differences in expression of progesterone receptor in oviduct and uterus of rabbit during early pregnancy.

We characterized the expression pattern of progesterone receptor (PR) in two regions of the oviduct (ampullae and isthmus), and the uterus (epithelium and stroma) of the rabbit (Oryctolagus cuniculus) during early pregnancy (1-4 days) by RT-PCR and immunohistochemistry. We observed a significant increase in the expression of PR at mRNA level in the uterus on days 1 and 2 of pregnancy, followed by a decrease on days 3 and 4. These changes were also observed at protein level in the uterine epithelium.

Changes in the content and distribution of microtubule associated protein 2 in the hippocampus of the rat during the estrous cycle.

The molecular mechanisms involved in the regulation of synaptic plasticity in the hippocampus during the estrous cycle of the rat are not completely understood. Because this process implicates changes in neuronal cytoskeleton organization, we analyzed the content of microtubule associated protein 2 (MAP2) and Tau in the hippocampus and the frontal cortex of the rat by Western blot, as well as the hippocampal distribution of MAP2 during the estrous cycle by immunohistochemistry. In the hippocampus the lowest content of MAP2 was found on diestrus day, and it significantly increased at proestrus.

Estradiol and progesterone modify microtubule associated protein 2 content in the rat hippocampus.

The molecular mechanisms involved in the regulation of synaptic plasticity and neuroprotection by estradiol (E(2)) and progesterone (P(4)) are unknown. Because these processes involve changes in cytoskeleton organization, we studied the effects of E(2) and P(4) in the expression of two cytoskeletal proteins: microtubule associated protein 2 (MAP2) and tau in the hippocampus and the frontal cortex of ovariectomized adult rats. While tau expression was unaffected by E(2) and P(4), an increase in MAP2 protein content in the hippocampus but not in the cortex was observed after E(2) and P(4) treatments.