NONGENOMIC ACTIONS OF THYROID-HORMONE

Nongenomic actions of thyroid hormone are by definition independent of nuclear receptors for the hormone and have been described at the plas ma membrane, various cell organelles, the cytoskeleton, and in cytopla sm. The actions include alterations in solute transport (Ca2+, Na+, gl ucose), changes in activities of several kinases, including protein ki nase C, cAMP-dependent protein kinase and pyruvate kinase M(2) (PKM(2) ), effects on efficiency of specific mRNA translation and mRNA t(1/2), modulation of mitochondrial respiration, and regulation of actin poly merization (promotion of formation of F-actin). Iodothyronines also ca n regulate nongenomically the state of contractile elements in vascula r smooth muscle cells (VSMC). The physiologic significance at the cell ular level of certain of these actions has been demonstrated, for exam ple, in the cases of myocardiocyte Na+ current, red cell Ca2+ content, and the control by hormone-induced alterations in actin solubility of cell surface activity of iodothyronine 5'-monodeiodinase activity and the intracellular distribution of protein disulfide isomerase activit y. The physiologic significance of these actions at the organ or syste m level is less clear, but extranuclear effects of thyroid hormone on myocardial Na+ channel, sarcoplasmic reticulum Ca2+-ATPase activity, a nd contractile state of VSMC may each contribute to acute effects of t hyroid hormone on cardiac output that have recently been described cli nically. The molecular mechanisms for nongenomic actions are incomplet ely understood; relevant binding sites and signal transduction pathway s have been described for hormone actions on plasma membrane Ca2+-ATPa se activity, and PKM(2) monomer is known to bind T-3 and, as a result, prevent activation of the kinase via tetramer formation. Nongenomic a ctions of thyroid hormone may have different structure-activity relati onships of iodothyronines from those effects that depend upon nuclear receptors; they may have different time courses and may invoke complex signal transduction pathways before the action is detected.