Nongenomic actions of thyroid hormones: from basic research to clinical applications. An update.

Extranuclear or nongenomic actions of thyroid hormones are unaffected by the inhibitors of protein synthesis, their site of action has been localized at the plasma membrane but also in the cytoplasm and organelles such as the mitochondria. This review takes into account recent major advances in nongenomic effects of thyroid hormones in nervous system, immune system and cardiovascular tissue, with a particular focus on the plasma membrane receptor integrin αvβ3. In nerve cells nongenomic effects of thyroid hormones point mainly to a direct modulation of several channels/receptors for the major neurotransmitters, even though more complex pathways have also been demonstrated. Certain neuroprotective actions have recently been described for thyronamines, and this may be relevant to Alzheimer's disease and multiple sclerosis. The immune system is also modulated nongenomically by thyroid hormones, through potentiation of the effects of cytokines such as IFN-γ or lipopolysaccharide, or through activators of STAT protein leading to activation of the mammalian target of rapamycin (mTOR) pathway, a highly conserved kinase downstream target of nongenomic actions of thyroid hormone. The mTOR system is also involved in the cardioprotection mechanisms, where thyroid hormone signaling through the receptor integrin αvβ3 may play an important role that needs to be further studied. The identification of integrin αvβ3 as a plasma membrane receptor for thyroid hormones has provided a new perspective on the role of these hormones in cellular defense. Analogs of thyroid hormones, inhibitors and agonists at the integrin receptor for the hormone and mTOR inhibitors are evaluated as areas of emphasis for therapeutic research.