The thyroid hormone receptors are members of nuclear hormone receptor superfamily. Nuclear hormone receptors function as ligand inducible transcription factors capable of acting as co-repressors and/or co-activators for gene expression. Nuclear receptors contain a series of conserved domains or regions. These domains/regions include a variable NH2-domain (A/B region), a conserved DNAbinding domain (DBD or region C), a linker region (region D), a ligand binding domain (LBD or region E), and in some receptors a variable COOH-terminal (region F). The TR DNA binding domain recognizes and interacts with the thyroid hormone response elements (TREs). TR can bind to this half-site, AGGTCA, as a monomer, a homodimer, or a heterodimer with the RXR. The TR/RXR heterodimer is associated with corepressor proteins at the TRE in the absence of ligand. Upon binding of thyroid hormone, TR undergoes a conformational change, releasing corepressor proteins and allowing for the interaction with coactivator proteins that enhance TRE-driven gene transcription.
Thyroid hormones (TH) have important effects on development, growth, and metabolism. They are encoded by two different genes, alpha and beta. Their effect is mediated principally through T3, which regulates gene expression by binding to the TH receptors (TR)-α and –β. Thyroid hormones affect most mammalian tissues. In excess, these hormones may cause weight loss, tachycardia, atrial arrhythmias, and heart failure. Studies of TR isoform-specific knockout mice and patients with resistance to thyroid hormone syndrome suggest that TR-α mediates the effects of thyroid hormone on heart rate.