Endocrine Abstracts

The classical genomic actions of triiodothyronine (T₃) are mediated by high-affinity nuclear receptors that directly regulate gene expression. By contrast, the non-genomic effects of thyroid hormones occur rapidly and are unaffected by inhibitors of transcription and protein synthesis. The genomic actions of thyroid hormone have an established role in the development, differentiation and homeostatic maintenance of target tissues. The THRA and THRB genes encode three thyroid hormone receptors (TRα1, TRβ1 and TRβ2) that bind T₃ and recognise specific thyroid hormone response elements (TREs) in the promoters of target genes. Unliganded-TRs bind TREs and co-repressors and maintain a local, transcriptionally non-permissive chromatin structure. T₃ binding results in a conformational change, dissociation of co-repressor, recruitment of co-activators and through chromatin remodelling generation of a transcriptionally permissive chromatin structure. The non-genomic actions of thyroid hormones involve multiple physiological processes in many different cell types and are thought to be mediated by induction of [Ca²⁺]_I, cyclic-AMP or the protein kinase signalling cascades. Sites of non-genomic action are localized to the plasma membrane, cytoplasm, cytoskeleton and sub-cellular organelles. Recent advances in the field have identified Integrin αvβ5 as a high affinity membrane receptor for T₄ which activates MAPK (ERK1/2) signalling and results in nuclear receptor phosphorylation, induction of angiogenesis and promotion of cell growth. Cytoplasmic T₃/TRβ1 has also been shown to activate phosphatidylinositol-3-kinase (PI3K) and post-transcriptionally regulate expression of hypoxia-inducable-factor-1α. Thyroid hormones are also major regulators of mitochondrial function and diiodothyronine (T₂) and T₃ are thought to mediate rapid thermogenic responses. T₂ binds and activates the mitochondrial cytochrome-c-oxidase Va, whereas T₃ binds two truncated TRα isoform (p28 and p43) in mitochondria. P28 co-localizes with the adenine nuclear translocase and uncoupling proteins while liganded-p43 binds mitochondrial-DNA response elements and regulates mitochondrial protein synthesis. Thus, thyroid hormones exert important physiological actions by both genomic and non-genomic effects.