The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone.
Among the most important functions of thyroid hormone receptors are regulation of metabolism and heart rate. In addition, they play critical roles in the development of organisms.
Mechanism of action
Thyroid hormone receptors regulate gene expression by binding to hormone response elements (HREs) in DNA either as monomers, heterodimers with retinoid X receptor (RXR; which in turn is activated by binding to 9-cis-retinoic acid) or as homodimers. However TR/RXR heterodimers are the most transcriptionally active form of TR.
In the absence of hormone, TR in complex with corepressor proteins bind to HREs in a transcriptionally inactive state. Binding of thyroid hormone results in a conformational change in TR which displaces corepressor from the receptor/DNA complex and recruitment of coactivator proteins. The DNA/TR/coactivator complex then recruits RNA polymerase that transcribes downstream DNA into messenger RNA and eventually protein that results in a change in cell function.
There are three forms of the thyroid hormone receptor designated alpha-1, beta-1 and beta-2 that are able to bind thyroid hormone. There are two TR-α receptor splice variants encoded by the THRA gene and two TR-β isoform splice variants encoded by the THRB gene:
- TR-α1 (widely expressed and especially high expression in cardiac and skeletal muscles)
- TR-α2 (homologous with viral oncogene c-erb-A, also widely expressed but unable to bind hormone)
- TR-β1 (predominately expressed in brain, liver and kidney)
- TR-β2 (expression primarily limited to the hypothalamus and pituitary)
Certain mutations in the thyroid hormone receptor are associated with thyroid hormone resistance.
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