title: The KCNQ1-KCNE2 K⁺ channel is required for adequate thyroid I⁻ uptake.
abstract: 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. The KCNQ1-specific antagonist (-)-[3R,4S]-chromanol 293B (C293B) significantly impaired thyroid cell I(-) uptake, which is mediated by the Na(+)/I(-) symporter (NIS), in vivo (dSUV/dt: vehicle, 0.028 ± 0.004 min(-1); 10 mg/kg C293B, 0.009 ± 0.006 min(-1)) and in vitro (EC(50): 99 ± 10 μM C293B). Na(+)-dependent nicotinate uptake by SMCT, however, was unaffected. Kcne2 deletion did not alter the balance of free vs. thyroglobulin-bound I(-) in the thyroid (distinguished using ClO(4)(-), a competitive inhibitor of NIS), indicating that KCNQ1-KCNE2 is not required for Duox/TPO-mediated I(-) organification. However, Kcne2 deletion doubled the rate of free I(-) efflux from the thyroid following ClO(4)(-) injection, a NIS-independent process. Thus, KCNQ1-KCNE2 is necessary for adequate thyroid cell I(-) uptake, the most likely explanation being that it is prerequisite for adequate NIS activity.
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Kerry
authors.initials: K
authors.lastname: Purtell
authors.forename: Monika
authors.initials: M
authors.lastname: Paroder-Belenitsky
authors.forename: Andrea
authors.initials: A
authors.lastname: Reyna-Neyra
authors.forename: Juan P
authors.initials: JP
authors.lastname: Nicola
authors.forename: Wade
authors.initials: W
authors.lastname: Koba
authors.forename: Eugene
authors.initials: E
authors.lastname: Fine
authors.forename: Nancy
authors.initials: N
authors.lastname: Carrasco
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Abbott
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics; D007454:Iodides / Q000378:metabolism*; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D049268:Positron-Emission Tomography; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism*; D000099209:Sodium-Iodide Symporters
chemical_list: D007454:Iodides; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C489620:Kcne2 protein, mouse; C496910:Kcnq1 protein, mouse