Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions

Triiodothyronine (T3) classically regulates gene expression by binding to high-affinity thyroid hormone receptors (TR) that recognize specific response elements in the promoters of T3-target genes and activate or repress transcription in response to hormone. However, a number of thyroid hormone effects occur rapidly and are unaffected by inhibitors of transcription and translation, suggesting that thyroid hormones may also mediate non-genomic actions. Such actions have been described in many tissues and cell types, including brown adipose tissue, the heart and pituitary. The site of non-genomic hormone action has been localized to the plasma membrane, cytoplasm and cellular organelles. These non-genomic actions include the regulation of ion channels, oxidative phosphorylation and mitochondrial gene transcription and involve the generation of intracellular secondary messengers and induction of [Ca(2+)](I), cyclic AMP or protein kinase signalling cascades. These observations have been interpreted to imply the presence of a specific, membrane associated, TR isoform or an unrelated high affinity membrane receptor for thyroid hormone. The recent identification of a progestin membrane receptor and the sub cellular targeted nuclear receptor isoforms ER46, mtRXR, mtPPAR, p28 and p46, has highlighted the potential importance of non-genomic actions of steroid hormones. Here we compare these recently identified receptors with the genomic, non-genomic and mitochondrial actions of thyroid hormones and consider their implications.