Nongenomic Actions Extranuclear Actions

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A number of T3 effects occur rapidly and are unaffected by inhibitors of transcription and protein synthesis. The site of these actions has been localized to the plasma membrane, cytoplasm and cellular organelles. The nongenomic actions often have a short latency. Cell culture studies suggest that thyroid hormones rapidly, and nongenomically regulate the Ca2+ ATPase enzyme, the Na+ channel via protein kinase C (PKC), the K+ channel via phosphatidyl-inositol 3 (PI3)-kinase, the Na+/H+ antiporter via PKC and mitogen-activated protein kinase (MAPK) [98]. The nongenomic actions thus presumably include the regulation of ion channels, oxidative phosphorylation and mitochondrial gene transcription and involve the generation of intracellular secondary messengers signaling pathways including induction of calcium, cyclic AMP or protein kinase signaling cascades [91, 98-100]. Recently, integrin aVp3, has been identified as a plasma membrane TH-binding site [101]. Furthermore, it has been shown that both T4 and T3 activate MAPK activity leading to phosphory-lation of TRp [90]. Additionally Davis and colleagues [102, 103] showed a proangiogenic action of the thyroid hormone analogues GC-1 and 3,5'-diiodothyropropionic acid (DITPA) initiated at the cell surface interacting with integrin. The proposed model (represented schematically in fig. 5b) thus includes that TH activates the MAPK cascade and promotes angiogenesis via TH binding to membrane-bound integrin aVp3.

TH Analogs, Metabolites, and Antagonists

Several tissue- and TR isoform-specific compounds have been developed as potential treatments for hypercholesterolemia, obesity, and heart failure [reviewed in 96]. In the development of these compounds it is attempted to use information on tissue-specific uptake of the compound. One of the initial compounds was investigated in mice, who subsequently had lower serum cholesterol levels without cardiotoxicity. Recently, several other TH analogs have been described that have compared to TRa. Since thyroid hormone receptors in the liver, isoform-selective affinity for TRp is approximately 90% TRp, and in the heart mostly TRa, these isoform-selective compounds may serve as novel agents to lower serum cholesterol with minimal cardiotoxicity. Recently, KB141 was shown to be a potential treatment for obesity by decreasing body weight via stimulation of metabolic rate and oxygen consumption.

Some TH analogs and derivatives can also bind specifically to proteins other than thyroid hormone receptors, and are involved in nongenomic cell signaling pathways. Recently, Scanlan et al. [104] identified 3-iodothyronamine, which is a naturally occurring byproduct of TH, with interesting physiological actions as it produced a rapid drop in body temperature and heart rate when injected intraperitoneally in mice. These physiological actions are thus opposite of those observed for T3, and may provide a counter-regulation to the transcrip-tional effects of TH by nuclear thyroid hormone receptors.

The TH-related compound demonstrated with low metabolic activity and low affinity for nuclear thyroid hormone receptors, DITPA was able to increase cardiac contractility and peripheral circulation without significant effects on heart rate as well as improve hemodynamic performance in animal models of congestive heart failure after myocardial infarction [105]. Preliminary studies have been performed in patients with heart failure demonstrating a significant improvement in systolic cardiac index and systemic vascular resistance [106]. Future studies are needed with this and similar compounds to clarify if such drugs may represent a novel class of drugs for the treatment of heart failure.

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