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 plasma membrane, various cell organelles, the cytoskeleton, and in cytoplasm. The actions include alterations in solute transport (Ca 2+ , Na + , glucose), changes in activities of several kinases, including protein kinase 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 polymerization (promotion of formation of F-actin). Iodothyronines also can regulate nongenomically the state of contractile elements in vascular smooth muscle cells (VSMC). The physiologic significance at the cellular level of certain of these actions has been demonstrated, for example, in the cases of myocardiocyte Na + current, red cell Ca 2+ 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 activity. The physiologic significance of these actions at the organ or system level is less clear, but extranuclear effects of thyroid hormone on myocardial Na + channel, sarcoplasmic reticulum Ca 2+ -ATPase activity, and contractile state of VSMC may each contribute to acute effects of thyroid hormone on cardiac output that have recently been described clinically. The molecular mechanisms for nongenomic actions are incompletely understood; relevant binding sites and signal transduction pathways have been described for hormone actions on plasma membrane Ca 2+ -ATPase activity, and PKM 2 monomer is known to bind T 3 and, as a result, prevent activation of the kinase via tetramer formation. Nongenomic actions of thyroid hormone may have different structure-activity relationships 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.