Nongenomic effects of thyroid hormones on ion transport

Extranuclear or nongenomic effects of thyroid hormone are unaffected by the inhibitors of protein synthesis, and their time course cannot be explained by the interaction of the hormone molecule with nuclear receptors. Their site of action has been localized at the plasma membrane, but also at the cytoplasm and organelles such as the mitochondria. In particular thyroid hormone has been reported to activate, by both genomic and non genomic mechanism, the Ca2+-ATPase, an ion pump that removes calcium from the cytosol and stores it in the sarcoplasmic reticulum. The decrease in intracellular Ca2+ generated during the systole leads to cardiac muscle relaxation. Given to all these important effects on the cardiovascular system, T3 can be also envisaged as a potent novel therapeutic agent as a inotropic drug. Thyroid hormone is also a major regulator of the Na/K-ATPase activity in several tissues. L-T3 and its analog 3,5-diiodothyronine give rise to a fast inhibition of the Na+/K+-ATPase activity in chick embryo hepatocytes, whereas L-T4 appears to be ineffective. The Na/H exchanger, activated by the thyroid hormone by both genomic and nongenomic mechanism, is a ubiquitous plasma membrane integral protein exchanging extracellular Na+ with cytoplasmic H+ ions according to the concentration gradient; it does not require energy supply, but depends on the Na+/K+-ATPase. Some of these effects are mediated by PKC and MAPK pathway, likely interfaces between genomic and nongenomic effects of thyroid hormones. The extranuclear effects should be taken into account when considering appropriate therapeutic intervention based on thyroid hormone both for their possible reinforcement of the nuclear effects and for their fast time onset, that might be of clinical relevance particularly for the cardiovascular system.