Extranuclear effects of thyroid hormones
Thyroid hormones T3 and T4 have fundamental roles in development, differentiation and metabolism. Many of these actions can be explained by the well-known binding of T3 to specific nuclear receptors TRα and TRβ, which regulate the expression of numerous genes. However, more and more examples of extranuclear or nongenomic effects of thyroid hormones are now appearing, based on mechanisms that are independent of the nuclear receptors and protein synthesis. These rapid effects have their origin at the plasma membrane, the cytoskeleton, in mitochondria or in the cytosol. The αVβ3 integrin of the plasma membrane act as a thyroid hormone receptor, and the binding of T4 to the integrin Arg-Gly-Asp (RGD) recognition site gives rise to stimulation of tumor cell proliferation and angiogenesis, through activation of the MAPK pathway. Also T3 is able to bind to the integrin although with less affinity, but at variance with T4, T3 may bind to more than one site. The intracellular thyroid hormone receptors TRα and TRβ can shuttle between cytosol and nucleus, and mediate different types of extranuclear effects. This process can be affected by the αVβ3 integrin activity, showing that different thyroid hormone receptors may interact with each other. In particular thyroid hormones produce short-term effects on fundamental Na-dependent transport systems, such as the Na/H exchanger, the amino acid transport System A and the Na/K-ATPase, through signal transduction mechanisms involving protein kinase C, protein kinase A and phosphatidyl inositol-3 kinase pathways. A survey of the present scenario of nongenomic actions of thyroid hormones will be given, and the possible physiopathological implications of these findings will be discussed.