Molecular Basis of Nongenomic Actions of Thyroid Hormone

Nongenomic actions of thyroid hormone are initiated by the hormone at receptors in the plasma membrane, in cytoplasm, or in mitochondria and do not require the interaction of nuclear thyroid hormone receptors (TRs) with their primary ligand, 3,5,3'-triiodo-L-thyronine (T-3). Receptors involved in nongenomic actions may or may not have structural homologies with TRs. Certain nongenomic actions that originate at the plasma membrane may modify the state and function of intranuclear TRs. Reviewed here are nongenomic effects of the hormone-T-3 or, in some cases, L-thyroxine (T-4)-that are initiated at (a) truncated TRa isoforms, e.g., p30 TR alpha 1, (b) cytoplasmic proteins, or (c) plasma membrane integrin alpha v beta 3. p30 TR alpha 1 is not transcriptionally competent, binds T-3 at the cell surface, and consequently expresses a number of important functions in bone cells. Nongenomic hormonal control of mitochondrial respiration involves a TRa isoform, and another truncated TRa isoform nongenomically regulates the state of cellular actin. Cytoplasmic hormone-binding proteins involved in nongenomic actions of thyroid hormone include ketimine reductase, pyruvate kinase, and TR ss that shuttle among intracellular compartments. Functions of the receptor for T-4 on integrin alpha v beta 3 include stimulation of proliferation of cancer and endothelial cells (angiogenesis) and regulation of transcription of cancer cell survival pathway genes. T-4 serves as a prohormone for T-3 in genomic actions of thyroid hormone, but T-4 is a hormone at alpha v beta 3 and more important to cancer cell function than is T-3. Thus, characterization of nongenomic actions of the hormone has served to broaden our understanding of the cellular roles of T-3 and T-4.