Clark Adam A, Dotson Cedrick D, Elson Amanda E T, Voigt Anja, Boehm Ulrich, Meyerhof Wolfgang, Steinle Nanette I, Munger Steven D
Department of Anatomy and Neurobiology, Program in Toxicology.
Department of Anatomy and Neurobiology.
FASEB J. 2015 Jan;29(1):164-72. doi: 10.1096/fj.14-262246. Epub 2014 Oct 23.
Dysregulation of thyroid hormones triiodothyronine and thyroxine (T3/T4) can impact metabolism, body composition, and development. Thus, it is critical to identify novel mechanisms that impact T3/T4 production. We found that type 2 taste receptors (TAS2Rs), which are activated by bitter-tasting compounds such as those found in many foods and pharmaceuticals, negatively regulate thyroid-stimulating hormone (TSH)-dependent Ca(2+) increases and TSH-dependent iodide efflux in thyrocytes. Immunohistochemical Tas2r-dependent reporter expression and real-time PCR analyses reveal that human and mouse thyrocytes and the Nthy-Ori 3-1 human thyrocyte line express several TAS2Rs. Five different agonists for thyrocyte-expressed TAS2Rs reduced TSH-dependent Ca(2+) release in Nthy-Ori 3-1 cells, but not basal Ca(2+) levels, in a dose-dependent manner. Ca(2+) responses were unaffected by 6-n-propylthiouracil, consistent with the expression of an unresponsive variant of its cognate receptor, TAS2R38, in these cells. TAS2R agonists also inhibited basal and TSH-dependent iodide efflux. Furthermore, a common TAS2R42 polymorphism is associated with increased serum T4 levels in a human cohort. Our findings indicate that TAS2Rs couple the detection of bitter-tasting compounds to changes in thyrocyte function and T3/T4 production. Thus, TAS2Rs may mediate a protective response to overingestion of toxic materials and could serve as new druggable targets for therapeutic treatment of hypo- or hyperthyroidism.
甲状腺激素三碘甲状腺原氨酸和甲状腺素（T3/T4）的失调会影响新陈代谢、身体组成和发育。因此，识别影响T3/T4产生的新机制至关重要。我们发现，2型味觉受体（TAS2Rs）可被许多食物和药物中存在的苦味化合物激活，它对甲状腺细胞中促甲状腺激素（TSH）依赖性的Ca(2+)增加和TSH依赖性的碘外流起负调节作用。免疫组织化学Tas2r依赖性报告基因表达和实时PCR分析表明，人和小鼠的甲状腺细胞以及Nthy-Ori 3-1人甲状腺细胞系表达多种TAS2Rs。五种不同的甲状腺细胞表达的TAS2Rs激动剂以剂量依赖性方式降低了Nthy-Ori 3-1细胞中TSH依赖性的Ca(2+)释放，但不影响基础Ca(2+)水平。Ca(2+)反应不受6-正丙基硫氧嘧啶的影响，这与其同源受体TAS2R38的无反应变体在这些细胞中的表达一致。TAS2R激动剂也抑制基础和TSH依赖性的碘外流。此外，一种常见的TAS2R42多态性与人类队列中血清T4水平升高有关。我们的研究结果表明，TAS2Rs将苦味化合物的检测与甲状腺细胞功能和T3/T4产生的变化联系起来。因此，TAS2Rs可能介导对过量摄入有毒物质的保护反应，并可作为治疗甲状腺功能减退或亢进的新的可药物作用靶点。
