Nongenomic Actions of Thyroid Hormone Initiated at the Plasma Membrane or in Cytoplasm

Genomic actions of thyroid hormone are initiated with intranuclear binding of the hormone by heterodimeric nuclear thyroid hormone receptor (TR) proteins that are transcription factors. There is increasing recent experimental appreciation of the existence of nongenomic actions of the hormone that are initiated in cytoplasm or at the plasma membrane. Those that begin in cytoplasm may involve nuclear TRs now recognized to reside in cytoplasm and may alter the state of the actin cytoskeleton or foster insertion into the plasma membrane of the Na,K-ATPase; cytoplasmic action
of the hormone via TR may also culminate downstream in the nucleus in the transcription of specific genes, such as hypoxia-inducible factor-1α. A plasma membrane receptor for L-thyroxine (T4) and 3, 5, 3’-triiodo-L-thyronine (T3) has been described on integrin αvβ3. Among the complex mitogen-activated protein kinase (MAPK; ERK1/2)-mediated activities initiated at the integrin receptor are tumor cell proliferation and angiogenesis. Shuttling of TRs between cytoplasm and nucleus may be promoted by thyroid hormone via the integrin. The hormonal actions attributable to integrin-liganded T4 or T3 can be reproduced by hormone analogues tethered to agarose or to nanoparticles that prevent cell entry of the hormone. Tetraiodothyoacetic acid (tetrac) is an inhibitor of the actions of T4 and T3 at the integrin. Tetrac has anti-proliferative and antiangiogenic activities that are currently under exploration.