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 (Ca2+, Na+, glucose), changes in activities of 
several kinases, including protein kinase C, cAMP-dependent protein kinase and 
pyruvate kinase M2 (PKM2), effects on efficiency of specific mRNA translation 
and mRNA t1/2, 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 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 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 PKM2 monomer is 
known to bind T3 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.