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Suzuki
Differential regulation of apical and basal iodide transporters in the thyroid by thyroglobulin.Suzuki K, Kohn LD. J Endocrinol. 2006 May;189(2):247-55.
"We have shown that
thyroglobulin (Tg) is a potent autocrine regulator of
thyroid-specific gene expression, and proposed that the
accumulated follicular Tg within the colloid is a major factor in
determining follicular function. In the present report, we
examined the effect of Tg on the action of TSH/cAMP and iodine
with special focus on the regulation of basolateral and apical
iodide transporters; the sodium/iodide symporter (NIS) and the
pendred syndrome gene (PDS) by Tg. We show that expression of NIS
and PDS are differentially regulated by Tg concentration and
exposure time. In addition, we found that PDS gene was induced by
TSH/cAMP and iodide in the presence of Tg. Based on these
results, we propose a model for the physiological turnover of
follicular function that is dynamically regulated by Tg."
Mechanism of iodide/chloride exchange by pendrin.Yoshida A, Hisatome I, Taniguchi S, Sasaki N, Yamamoto Y, Miake J, Fukui H, Shimizu H, Okamura T, Okura T, Igawa O, Shigemasa C, Green ED, Kohn LD, Suzuki K. Endocrinology. 2004 Sep;145(9):4301-8. Epub 2004 May 20.
"We performed an
electrophysiological study to investigate ion transport of pendrin and
thereby understand the pathogenesis of Pendred syndrome. Using
pendrin-transfected COS-7 cells, we could show that pendrin transports
both iodide and chloride measured as voltage-dependent inward and
outward membrane currents. Chloride in the culture medium, [Cl-]o, was
efficiently exchanged with cytoplasmic iodide, [I-]i, under
physiological concentrations, indicating that pendrin is important for
chloride uptake and iodide efflux. Although exchange of iodide in the
medium, [I-]o, with cytoplasmic chloride, [Cl-]i, was observed, a
significantly high concentration of iodide (10 mm) was required. In
addition, either iodide or chloride was required on both sides of the
cell membrane for the anion exchange activity of pendrin, indicating
that iodide and chloride activate the exchange activity of pendrin
while they are transported. The present study further supports that
pendrin is responsible for the iodide efflux in thyroid cells where
intracellular iodide concentration is high and that the general
function of pendrin in other tissues is to transport chloride through
exchange with other anions."
Expression of human pendrin in diseased thyroids.Kondo T, Nakamura N, Suzuki K, Murata S, Muramatsu A, Kawaoi A, Katoh R. J Histochem Cytochem. 2003 Feb;51(2):167-73.
"We examined pendrin expression in various diseased thyroid tissues by immunohistochemistry (IHC) using antiserum raised against human pendrin and by real-time quantitative RT-PCR. In normal thyroids the antiserum reacted with the apical membrane of follicular cells and its immunoreactivity was faint. In Graves' thyroids, the IHC expression of pendrin appeared in a pattern similar to that of normal thyroids but it was more extensive and stronger, especially in areas showing marked proliferation of follicular cells. The immunoreactivities of pendrin in nodular goiters varied from case to case. In follicular adenomas, pendrin was localized in the follicle-forming parts of the tumor but was negative in trabecular parts. Pendrin was negative in all follicular carcinomas, papillary carcinomas, and in one case of medullary carcinoma. In quantitive mRNA analysis, the relative values of pendrin mRNA were significantly low in papillary carcinoma (p<0.01), whereas the values in other diseased thyroids were not significantly different from those in normal thyroids. These results suggest that pendrin may play a role in thyroid hormone production as the apical porter of chloride/iodide and investigation of pendrin leads to a better understanding of functional aspects of the iodine transportation system in thyroid diseases."
Pendrin is an iodide-specific apical porter responsible for iodide efflux from thyroid cells.Yoshida A, Taniguchi S, Hisatome I, Royaux IE, Green ED, Kohn LD, Suzuki K. J Clin Endocrinol Metab. 2002 Jul;87(7):3356-61.
"The Pendred syndrome gene encodes a 780-amino acid putative transmembrane protein (pendrin) that is expressed in the apical membrane of thyroid follicular cells. Although pendrin was shown to transport iodide and chloride using Xenopus laevis oocytes and Sf9 insect cells, there is no report using mammalian cells to study its role in thyroid function. We show here, using COS-7 cells and Chinese hamster ovary cells transfected with expression vectors encoding sodium iodide symporter or human Pendred syndrome gene cDNA and by comparison with studies using rat thyroid FRTL-5 cells, that pendrin is an iodide-specific transporter in mammalian cells and is responsible for iodide efflux in the thyroid."
Retention of pendrin in the endoplasmic reticulum is a major mechanism for Pendred syndrome.Rotman-Pikielny P, Hirschberg K, Maruvada P, Suzuki K, Royaux IE, Green ED, Kohn LD, Lippincott-Schwartz J, Yen PM. Hum Mol Genet. 2002 Oct 1;11(21):2625-33.
"Pendred syndrome is a major cause of congenital deafness, goiter and defective iodide organification. Mutations in the transmembrane protein, pendrin, cause diminished export of iodide from thyroid follicular cells to the colloid and are associated with the syndrome. We used green fluorescent protein (GFP) chimeras of wild-type (WT) pendrin and three common natural mutants (L236P, T416P and G384) to study their intracellular trafficking in living cells. Time-lapse imaging, dual color labeling and fluorescent recovery after photobleaching (FRAP) studies demonstrated that GFP-WT pendrin targets to the plasma membrane. In contrast, all three mutant pendrins were retained in the endoplasmic reticulum (ER) in co-localization studies with ER and Golgi markers. The ER retention of L236P appeared to be selective as this mutant did not prevent a viral membrane protein, VSVGtsO45 or wild-type pendrin from targeting the plasma membrane. These findings suggest that ER retention and defective plasma membrane targeting of pendrin mutants play a key role in the pathogenesis of Pendred syndrome."
Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion.Royaux IE, Wall SM, Karniski LP, Everett LA, Suzuki K, Knepper MA, Green ED. Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4221-6.
"Pendrin is an anion transporter encoded by the PDS/Pds gene. In humans, mutations in PDS cause the genetic disorder Pendred syndrome, which is associated with deafness and goiter. Previous studies have shown that this gene has a relatively restricted pattern of expression, with PDS/Pds mRNA detected only in the thyroid, inner ear, and kidney. The present study examined the distribution and function of pendrin in the mammalian kidney. Immunolocalization studies were performed using anti-pendrin polyclonal and monoclonal antibodies. Labeling was detected on the apical surface of a subpopulation of cells within the cortical collecting ducts (CCDs) that also express the H(+)-ATPase but not aquaporin-2, indicating that pendrin is present in intercalated cells of the CCD. Furthermore, pendrin was detected exclusively within the subpopulation of intercalated cells that express the H(+)-ATPase but not the anion exchanger 1 (AE1) and that are thought to mediate bicarbonate secretion. The same distribution of pendrin was observed in mouse, rat, and human kidney. However, pendrin was not detected in kidneys from a Pds-knockout mouse. Perfused CCD tubules isolated from alkali-loaded wild-type mice secreted bicarbonate, whereas tubules from alkali-loaded Pds-knockout mice failed to secrete bicarbonate. Together, these studies indicate that pendrin is an apical anion transporter in intercalated cells of CCDs and has an essential role in renal bicarbonate secretion."
Expression of PDS/Pds, the Pendred syndrome gene, in endometrium.Suzuki K, Royaux IE, Everett LA, Mori-Aoki A, Suzuki S, Nakamura K, Sakai T, Katoh R, Toda S, Green ED, Kohn LD. J Clin Endocrinol Metab. 2002 Feb;87(2):938.
"Expression of the Pendred
syndrome gene (PDS/Pds) is thought to be responsible for the iodide
transport in the thyroid as well as the formation and function of the
inner ear. Its mRNA is also expressed in the kidney and placenta. We
report here that PDS and its encoded protein (pendrin) are also
expressed in the endometrium. The RNA levels of rat PDS in the
endometrium and kidney were much higher than those of the thyroid,
opposite of the pattern of RNA expression in humans. In human
endometrium, pendrin localization changed from the basal to apical
surfaces of the epithelium during progression of the menstrual cycle.
This suggests a possible role for pendrin in cationic ion transport
required to maintain the physiological function of the endometrium.
Since there is no evidence of endometrial abnormalities in patients
with Pendred syndrome, it suggests the existence of a compensatory
mechanisms for pendrin's function in the uterus."
Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion.Royaux IE, Wall SM, Karniski LP, Everett LA, Suzuki K, Knepper MA, Green ED. Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4221-6.
"Pendrin is an anion transporter encoded by the PDS/Pds gene. In humans, mutations in PDS cause the genetic disorder Pendred syndrome, which is associated with deafness and goiter. Previous studies have shown that this gene has a relatively restricted pattern of expression, with PDS/Pds mRNA detected only in the thyroid, inner ear, and kidney. The present study examined the distribution and function of pendrin in the mammalian kidney. Immunolocalization studies were performed using anti-pendrin polyclonal and monoclonal antibodies. Labeling was detected on the apical surface of a subpopulation of cells within the cortical collecting ducts (CCDs) that also express the H(+)-ATPase but not aquaporin-2, indicating that pendrin is present in intercalated cells of the CCD. Furthermore, pendrin was detected exclusively within the subpopulation of intercalated cells that express the H(+)-ATPase but not the anion exchanger 1 (AE1) and that are thought to mediate bicarbonate secretion. The same distribution of pendrin was observed in mouse, rat, and human kidney. However, pendrin was not detected in kidneys from a Pds-knockout mouse. Perfused CCD tubules isolated from alkali-loaded wild-type mice secreted bicarbonate, whereas tubules from alkali-loaded Pds-knockout mice failed to secrete bicarbonate. Together, these studies indicate that pendrin is an apical anion transporter in intercalated cells of CCDs and has an essential role in renal bicarbonate secretion."
Effects of thyroglobulin and pendrin on iodide flux through the thyrocyte.Kohn LD, Suzuki K, Nakazato M, Royaux I, Green ED. Trends Endocrinol Metab. 2001 Jan-Feb;12(1):10-6. Review. [abstract only]
"Iodide transport by thyrocytes involves porters on the apical and basal surfaces of the cell facing the follicular lumen and bloodstream, respectively. Recent work identifies pendrin as an apical porter and shows that follicular thyroglobulin is a transcriptional regulator of the gene encoding pendrin and other thyroid-restricted genes. For example, whereas follicular thyroglobulin suppresses the gene expression and activity of the sodium iodide symporter (NIS), it increases pendrin gene expression. A potential new dynamic for iodide flux and thyroid hormone formation in thyrocytes has thus emerged and is supported by in vivo data."
Pendrin, the protein encoded by the Pendred syndrome gene (PDS), is an apical porter of iodide in the thyroid and is regulated by thyroglobulin in FRTL-5 cells.Royaux IE, Suzuki K, Mori A, Katoh R, Everett LA, Kohn LD, Green ED. Endocrinology. 2000 Feb;141(2):839-45.
"Pendred syndrome is an autosomal recessive disorder characterized by congenital deafness and thyroid goiter. The thyroid disease typically develops around puberty and is associated with a mild organification defect, characterized by an inappropriate discharge of iodide upon perchlorate stimulation (a positive perchlorate discharge test). The gene (PDS) mutated in Pendred syndrome is expressed in thyroid and encodes a 780-amino acid protein (pendrin) that has recently been shown to function as an iodide/chloride transporter. We sought to establish the location of pendrin in the thyroid and to examine the regulatory network controlling its synthesis. Using peptide-specific antibodies for immunolocalization studies, pendrin was detected in a limited subset of cells within the thyroid follicles, exclusively at the apical membrane of the follicular epithelium. Interestingly, significantly greater amounts of pendrin were encountered in thyroid tissue from patients with Graves' disease. Using a cultured rat thyroid cell line (FRTL-5), PDS expression was found to be significantly induced by low concentrations of thyroglobulin (TG), but not by TSH, sodium iodide, or insulin. This is different from the established effect of TG, more typically a potent suppressor of thyroid-specific gene expression. Together, these results suggest that pendrin is an apical porter of iodide in the thyroid and that the expression and function of both the apical and basal iodide porters are coordinately regulated by follicular TG."
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