Noncanonical Action of Thyroid Hormone Receptors α and β

Abstract

Thyroid hormone (TH) is essential for the regulation of many physiological processes, especially growth, organ development, energy metabolism and cardiovascular effects. TH acts via the TH receptors (TR) α and β. By binding to thyroid hormone responsive elements (TREs) on the DNA, TRs regulate expression of TH target genes. Thus, TRs are mainly characterized as ligand dependent transcription factors and regulation of gene expression and protein synthesis is considered the canonical mode of TH/TR action. The demonstration that the ligand-bound TRs α and β also mediate activation of the phosphatidylinositol-3-kinase (PI3K) pathway established noncanonical TH/TR action as an additional mode of TH signaling. Recently, TR mutant mouse models allowed to determine the underlying mode of TH/TR action, either canonical or noncanonical TH/TR signaling, for several physiological TH effects in vivo: Regulation of the hypothalamic-pituitary-thyroid axis requires DNA-binding of TRβ, whereas hepatic triglyceride content appears to be regulated by noncanonical TRβ signaling. TRα mediated effects in bone development are dependent on DNA-binding, whereas several cardiovascular TRα effects are rapid and independent from DNA-binding. Therefore, noncanonical TH/TR action contributes to the overall effects of TH in physiology.

The disturbance of thyroid-associated hormone and its receptors in brain and blood circulation existed in the early stage of mouse model of Alzheimer’s disease

“…Finally, T3 binds to its nuclear TH receptors (TRs), before the target genes are repressively inhibited or activated [ 33 ]. Our results suggest that the increased expression of THRα and β and their genes in the brain tissue of the mice in the experimental group may also be the mechanism of the repair response in mice at the early stage of the AD model, but further evidence is needed, which is consistent with the results reported previously [ 34 ], but contrary to the results in another report [ 35 ], the most likely reason is that the hypothalamic-pituitary-thyroid axis modulates thyroid function by a negative feedback mechanism [ 36 , 37 ]. When FT3 or FT4 is elevated, the negative feedback inhibits the concentrations of TSH and TRH and keeps the FT3 and FT4 of thyroid secretion in the normal range.…”

Seven Years of Active Thyroid Hormone Research in Germany: Thyroid Hormone Action beyond Classical Concepts

“…nuclear as well non-canonical, i.e. cytosolic action, as first demonstrated in vivo in elegant mouse models established by the Moeller group [12].…”

“…Regulation of body temperature as investigated by Mittag and co-workers [13], influence on brain structure and function studied by the Münte group [14], browning of white adipose tissue analysed by Krause and coworkers [15], autoregulation of the thyroid gland investigated by the Brix group [16], TH action in bone remodelling studied by Rauner and team [17], as well as the role of TH in ageing or male and female organisms as deciphered by Führer and coworkers [3] highlight the impressive spectrum of TH action in an organism, for which a new understanding was reached by the work of TTA. In addition, TH plays a role in a variety of pathophysio logical processes such as tumour formation, investigated by the Spitzweg & Nelson team [18], biliary disease as demonstrated by Zwanziger and coworkers [19], and cardiovascular disorders as shown collectively in mouse models by the TTA groups of Mittag, Führer and Möller [3,12,13].…”

The interplay of thyroid hormones and the immune system – where we stand and why we need to know about it

“…Three main T3-binding THR isoforms have been identified to date, THRa1, THRb1 and THRb2. In addition to this classical concept of canonical mode of action, THRs may additionally act via noncanonical signalling ( 30 , 31 , 32 , 33 , 34 , 35 ). Here, activation of rapid cytosolic signalling cascades, for instance phosphatidylinositol-3-kinase (PI3K) or extracellular-signal-regulated kinase (ERK) pathways, are mediated by ligand-bound THRs.…”