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

The KCNQ1 α subunit and the KCNE2 βsubunit 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 (EC₅₀: 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 ClO₄^- 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.